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Sample records for pancreatic tumor motion

  1. Considerable pancreatic tumor motion during breath-holding.

    PubMed

    Lens, Eelco; van der Horst, Astrid; Versteijne, Eva; Bel, Arjan; van Tienhoven, Geertjan

    2016-11-01

    Breath-holding (BH) is often used to reduce abdominal organ motion during radiotherapy. However, for inhale BH, abdominal tumor motion during BH has not yet been investigated. The aim of this study was to quantify tumor motion during inhale BH and tumor position variations between consecutive inhale BHs in pancreatic cancer patients. Twelve patients with intratumoral fiducials were included and asked to perform three consecutive 30-second inhale BHs on each of three measurement days. During BH, lateral fluoroscopic movies were obtained and a two-dimensional (2D) image correlation algorithm was used to track the fiducials and the diaphragm, yielding the tumor and diaphragm motion during each BH. The tumor position variation between consecutive BHs was obtained from the difference in initial tumor position between consecutive BHs on a single measurement day. We observed tumor motion during BH with a mean absolute maximum displacement over all BHs of 4.2 mm (range 1.0-11.0 mm) in inferior-superior (IS) direction and 2.7 mm (range 0.5-8.0 mm) in anterior-posterior (AP) direction. We found only a moderate correlation between tumor and diaphragm motion in the IS direction (Pearson's correlation coefficient |r|>0.6 in 45 of 76 BHs). The mean tumor position variation between consecutive BHs was 0.2 [standard deviation (SD) 1.7] mm in the inferior direction and 0.5 (SD 0.8) mm in the anterior direction. We observed substantial pancreatic tumor motion during BH as well as considerable position variation between consecutive BHs on a single day. We recommend further quantifying these uncertainties before introducing breath-hold during radiation treatment of pancreatic cancer patients. Also, the diaphragm cannot be used as a surrogate for pancreatic tumor motion.

  2. Characterization of Pancreatic Tumor Motion Using Cine MRI: Surrogates for Tumor Position Should Be Used With Caution

    SciTech Connect

    Feng, Mary Balter, James M.; Normolle, Daniel; Adusumilli, Saroja; Cao Yue; Chenevert, Thomas L.; Ben-Josef, Edgar

    2009-07-01

    Purpose: Our current understanding of intrafraction pancreatic tumor motion due to respiration is limited. In this study, we characterized pancreatic tumor motion and evaluated the application of several radiotherapy motion management strategies. Methods and Materials: Seventeen patients with unresectable pancreatic cancer were enrolled in a prospective internal review board-approved study and imaged during shallow free-breathing using cine MRI on a 3T scanner. Tumor borders were agreed on by a radiation oncologist and an abdominal MRI radiologist. Tumor motion and correlation with the potential surrogates of the diaphragm and abdominal wall were assessed. These data were also used to evaluate planning target volume margin construction, respiratory gating, and four-dimensional treatment planning for pancreatic tumors. Results: Tumor borders moved much more than expected. To provide 99% geometric coverage, margins of 20 mm inferiorly, 10 mm anteriorly, 7 mm superiorly, and 4 mm posteriorly are required. Tumor position correlated poorly with diaphragm and abdominal wall position, with patient-level Pearson correlation coefficients of -0.18-0.43. Sensitivity and specificity of gating with these surrogates was also poor, at 53%-68%, with overall error of 35%-38%, suggesting that the tumor may be underdosed and normal tissues overdosed. Conclusions: Motion of pancreatic tumor borders is highly variable between patients and larger than expected. There is substantial deformation with breathing, and tumor border position does not correlate well with abdominal wall or diaphragmatic position. Current motion management strategies may not account fully for tumor motion and should be used with caution.

  3. MRI-based tumor motion characterization and gating schemes for radiation therapy of pancreatic cancer.

    PubMed

    Heerkens, Hanne D; van Vulpen, Marco; van den Berg, Cornelis A T; Tijssen, Rob H N; Crijns, Sjoerd P M; Molenaar, Izaak Q; van Santvoort, Hjalmar C; Reerink, Onne; Meijer, Gert J

    2014-05-01

    To characterize pancreatic tumor motion and to develop a gating scheme for radiotherapy in pancreatic cancer. Two cine MRIs of 60s each were performed in fifteen pancreatic cancer patients, one in sagittal direction and one in coronal direction. A Minimum Output Sum of Squared Error (MOSSE) adaptive correlation filter was used to quantify tumor motion in craniocaudal, lateral and anteroposterior directions. To develop a gating scheme, stability of the breathing phases was examined and a gating window assessment was created, incorporating tumor motion, treatment time and motion margins. The largest tumor motion was found in craniocaudal direction, with an average peak-to-peak amplitude of 15mm (range 6-34mm). Amplitude of the tumor in the anteroposterior direction was on average 5mm (range 1-13mm). The least motion was seen in lateral direction (average 3mm, range 2-5mm). The end exhale position was the most stable position in the breathing cycle and tumors spent more time closer to the end exhale position than to the end inhale position. On average, a margin of 25% of the maximum craniocaudal breathing amplitude was needed to achieve full target coverage with a duty cycle of 50%. When reducing the duty cycle to 50%, a margin of 5mm was sufficient to cover the target in 11 out of 15 patients. Gated delivery for radiotherapy of pancreatic cancer is best performed around the end exhale position as this is the most stable position in the breathing cycle. Considerable margin reduction can be established at moderate duty cycles, yielding acceptable treatment efficiency. However, motion patterns and amplitude do substantially differ between individual patients. Therefore, individual treatment strategies should be considered for radiotherapy in pancreatic cancer. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  4. Pancreatic Tumor Growth Prediction with Multiplicative Growth and Image-Derived Motion.

    PubMed

    Wong, Ken C L; Summers, Ronald M; Kebebew, Electron; Yao, Jianhua

    2015-01-01

    Pancreatic neuroendocrine tumors are abnormal growths of hormone-producing cells in the pancreas. Different from the brain in the skull, the pancreas in the abdomen can be largely deformed by the body posture and the surrounding organs. In consequence, both tumor growth and pancreatic motion attribute to the tumor shape difference observable from images. As images at different time points are used to personalize the tumor growth model, the prediction accuracy may be reduced if such motion is ignored. Therefore, we incorporate the image-derived pancreatic motion to tumor growth personalization. For realistic mechanical interactions, the multiplicative growth decomposition is used with a hyperelastic constitutive law to model tumor mass effect, which allows growth modeling without compromising the mechanical accuracy. With also the FDG-PET and contrast-enhanced CT images, the functional, structural, and motion data are combined for a more patient-specific model. Experiments on synthetic and clinical data show the importance of image-derived motion on estimating physiologically plausible mechanical properties and the promising performance of our framework. From six patient data sets, the recall, precision, Dice coefficient, relative volume difference, and average surface distance were 89.8 ± 3.5%, 85.6 ± 7.5%, 87.4 ± 3.6%, 9.7 ± 7.2%, and 0.6 ± 0.2 mm, respectively.

  5. Optimizing 4-Dimensional Magnetic Resonance Imaging Data Sampling for Respiratory Motion Analysis of Pancreatic Tumors

    SciTech Connect

    Stemkens, Bjorn; Tijssen, Rob H.N.; Senneville, Baudouin D. de

    2015-03-01

    Purpose: To determine the optimum sampling strategy for retrospective reconstruction of 4-dimensional (4D) MR data for nonrigid motion characterization of tumor and organs at risk for radiation therapy purposes. Methods and Materials: For optimization, we compared 2 surrogate signals (external respiratory bellows and internal MRI navigators) and 2 MR sampling strategies (Cartesian and radial) in terms of image quality and robustness. Using the optimized protocol, 6 pancreatic cancer patients were scanned to calculate the 4D motion. Region of interest analysis was performed to characterize the respiratory-induced motion of the tumor and organs at risk simultaneously. Results: The MRI navigator was found to be a more reliable surrogate for pancreatic motion than the respiratory bellows signal. Radial sampling is most benign for undersampling artifacts and intraview motion. Motion characterization revealed interorgan and interpatient variation, as well as heterogeneity within the tumor. Conclusions: A robust 4D-MRI method, based on clinically available protocols, is presented and successfully applied to characterize the abdominal motion in a small number of pancreatic cancer patients.

  6. Modeling Pancreatic Tumor Motion Using 4-Dimensional Computed Tomography and Surrogate Markers

    SciTech Connect

    Huguet, Florence; Yorke, Ellen D.; Davidson, Margaret; Zhang, Zhigang; Jackson, Andrew; Mageras, Gig S.; Wu, Abraham J.; Goodman, Karyn A.

    2015-03-01

    Purpose: To assess intrafractional positional variations of pancreatic tumors using 4-dimensional computed tomography (4D-CT), their impact on gross tumor volume (GTV) coverage, the reliability of biliary stent, fiducial seeds, and the real-time position management (RPM) external marker as tumor surrogates for setup of respiratory gated treatment, and to build a correlative model of tumor motion. Methods and Materials: We analyzed the respiration-correlated 4D-CT images acquired during simulation of 36 patients with either a biliary stent (n=16) or implanted fiducials (n=20) who were treated with RPM respiratory gated intensity modulated radiation therapy for locally advanced pancreatic cancer. Respiratory displacement relative to end-exhalation was measured for the GTV, the biliary stent, or fiducial seeds, and the RPM marker. The results were compared between the full respiratory cycle and the gating interval. Linear mixed model was used to assess the correlation of GTV motion with the potential surrogate markers. Results: The average ± SD GTV excursions were 0.3 ± 0.2 cm in the left-right direction, 0.6 ± 0.3 cm in the anterior-posterior direction, and 1.3 ± 0.7 cm in the superior-inferior direction. Gating around end-exhalation reduced GTV motion by 46% to 60%. D95% was at least the prescribed 56 Gy in 76% of patients. GTV displacement was associated with the RPM marker, the biliary stent, and the fiducial seeds. The correlation was better with fiducial seeds and with biliary stent. Conclusions: Respiratory gating reduced the margin necessary for radiation therapy for pancreatic tumors. GTV motion was well correlated with biliary stent or fiducial seed displacements, validating their use as surrogates for daily assessment of GTV position during treatment. A patient-specific internal target volume based on 4D-CT is recommended both for gated and not-gated treatment; otherwise, our model can be used to predict the degree of GTV motion.

  7. Pancreatic Tumor Growth Prediction With Elastic-Growth Decomposition, Image-Derived Motion, and FDM-FEM Coupling.

    PubMed

    Wong, Ken C L; Summers, Ronald M; Kebebew, Electron; Yao, Jianhua

    2017-01-01

    Pancreatic neuroendocrine tumors are abnormal growths of hormone-producing cells in the pancreas. Unlike the brain which is protected by the skull, the pancreas can be significantly deformed by its surrounding organs. Consequently, the tumor shape differences observable from images at different time points arise from both tumor growth and pancreatic motion, and tumor growth model personalization may be compromised if such motion is ignored. Therefore, we incorporate pancreatic motion information derived from deformable image registration in model personalization. For more accurate mechanical interactions between tumor growth and pancreatic motion, elastic-growth decomposition is used with a hyperelastic constitutive law to model the mass effect, which allows growth modeling while conserving the mechanical properties. Furthermore, a way of coupling the finite difference method and the finite element method is proposed to greatly reduce the computation time. With both 2-[(18)F]-fluoro-2-deoxy-D-glucose positron emission tomographic and contrast-enhanced computed tomographic images, functional, structural, and motion data are combined for a patient-specific model. Experiments on synthetic and clinical data show the importance of image-derived motion on estimating pathophysiologically plausible mechanical properties and the promising performance of our framework. From seven patient data sets, the recall, precision, Dice coefficient, relative volume difference, and average surface distance between the personalized tumor growth simulations and the measurements were 83.2 ±8.8%, 86.9 ±8.3%, 84.4 ±4.0%, 13.9 ±9.8%, and 0.6 ±0.1 mm, respectively.

  8. Pancreatic neuroendocrine tumors

    PubMed Central

    Sun, Jian

    2017-01-01

    Summary Pancreatic neuroendocrine neoplasms (pNENs) are a heterogeneous group of tumors including well differentiated pancreatic neuroendocrine tumors (pNETs) and neuroendocrine carcinomas (pNECs). The incidence of pNENs has increased over the past few decades. Although, the understanding and interest for this tumor have also increased significantly, the debate about classification and diagnosis continues. Although the primary treatment for pNENs is surgical resection, there is still a lack of effective therapeutic options for patients with advanced unresectable pNENs. Although many therapeutic methods have proven effective, the choice of treatment and specific programs are still unclear. Our article presents an overview of pNENs, with a focus on their diagnostic work-up, clinical presentation and treatment options. PMID:28357177

  9. Harmonic Motion Imaging for Abdominal Tumor Detection and High-intensity Focused Ultrasound Ablation Monitoring: A Feasibility Study in a Transgenic Mouse Model of Pancreatic Cancer

    PubMed Central

    Chen, Hong; Hou, Gary Y.; Han, Yang; Payen, Thomas; Palermo, Carmine F.; Olive, Kenneth P.; Konofagou, Elisa E.

    2015-01-01

    Harmonic motion imaging (HMI) is a radiation force-based elasticity imaging technique that tracks oscillatory tissue displacements induced by sinusoidal ultrasonic radiation force to assess relative tissue stiffness. The objective of this study was to evaluate the feasibility of HMI in pancreatic tumor detection and high-intensity focused ultrasound (HIFU) treatment monitoring. The HMI system consisted of a focused ultrasound transducer, which generated sinusoidal radiation force to induce oscillatory tissue motion at 50 Hz, and a diagnostic ultrasound transducer, which detected the axial tissue displacements based on acquired radiofrequency signals using a 1D cross-correlation algorithm. For pancreatic tumor detection, HMI images were generated for pancreatic tumors in transgenic mice and normal pancreases in wild-type mice. The obtained HMI images showed a high contrast between normal and malignant pancreases with an average peak-to-peak HMI displacement ratio of 3.2. Histological analysis showed that no tissue damage was associated with HMI when it was used for the sole purpose of elasticity imaging. For pancreatic tumor ablation monitoring, the focused ultrasound transducer was operated with a higher acoustic power and longer pulse length than that used in tumor detection to simultaneously induce HIFU thermal ablation and oscillatory tissue displacements, allowing HMI monitoring without interrupting tumor ablation. HMI monitoring of HIFU ablation found significant decreases in the peak-to-peak HMI displacements before and after HIFU ablation with a reduction rate ranging from 15.8% to 57.0%. The formation of thermal lesions after HIFU exposure was confirmed by histological analysis. This study demonstrated the feasibility of HMI in abdominal tumor detection and HIFU ablation monitoring. PMID:26415128

  10. Harmonic motion imaging for abdominal tumor detection and high-intensity focused ultrasound ablation monitoring: an in vivo feasibility study in a transgenic mouse model of pancreatic cancer.

    PubMed

    Chen, Hong; Hou, Gary Y; Han, Yang; Payen, Thomas; Palermo, Carmine F; Olive, Kenneth P; Konofagou, Elisa E

    2015-09-01

    Harmonic motion imaging (HMI) is a radiationforce- based elasticity imaging technique that tracks oscillatory tissue displacements induced by sinusoidal ultrasonic radiation force to assess the resulting oscillatory displacement denoting the underlying tissue stiffness. The objective of this study was to evaluate the feasibility of HMI in pancreatic tumor detection and high-intensity focused ultrasound (HIFU) treatment monitoring. The HMI system consisted of a focused ultrasound transducer, which generated sinusoidal radiation force to induce oscillatory tissue motion at 50 Hz, and a diagnostic ultrasound transducer, which detected the axial tissue displacements based on acquired radio-frequency signals using a 1-D cross-correlation algorithm. For pancreatic tumor detection, HMI images were generated for pancreatic tumors in transgenic mice and normal pancreases in wild-type mice. The obtained HMI images showed a high contrast between normal and malignant pancreases with an average peak-to-peak HMI displacement ratio of 3.2. Histological analysis showed that no tissue damage was associated with HMI when it was used for the sole purpose of elasticity imaging. For pancreatic tumor ablation monitoring, the focused ultrasound transducer was operated at a higher acoustic power and longer pulse length than that used in tumor detection to simultaneously induce HIFU thermal ablation and oscillatory tissue displacements, allowing HMI monitoring without interrupting tumor ablation. HMI monitoring of HIFU ablation found significant decreases in the peak-to-peak HMI displacements before and after HIFU ablation with a reduction rate ranging from 15.8% to 57.0%. The formation of thermal lesions after HIFU exposure was confirmed by histological analysis. This study demonstrated the feasibility of HMI in abdominal tumor detection and HIFU ablation monitoring.

  11. SU-C-210-04: Considerable Pancreatic Tumor Motion During Breath-Hold Measured Using Intratumoral Fiducials On Fluoroscopic Movies

    SciTech Connect

    Lens, E; Horst, A van der; Versteijne, E; Tienhoven, G van; Bel, A

    2015-06-15

    Purpose: Using a breath hold (BH) technique during radiotherapy of pancreatic tumors is expected to reduce intra-fractional motion. The aim of this study was to evaluate the tumor motion during BH. Methods: In this pilot study, we included 8 consecutive pancreatic cancer patients. All had 2– 4 intratumoral gold fiducials. Patients were asked to perform 3 consecutive 30-second end-inhale BHs on day 5, 10 and 15 of their three-week treatment. During BH, airflow through a mouthpiece was measured using a spirometer. Any inadvertent flow of air during BH was monitored for all patients. We measured tumor motion on lateral fluoroscopic movies (57 in total) made during BH. In each movie the fiducials as a group were tracked over time in superior-inferior (SI) and anterior-posterior (AP) direction using 2-D image correlation between consecutive frames. We determined for each patient the range of intra-BH motion over all movies; we also determined the absolute means and standard deviations (SDs) for the entire patient group. Additionally, we investigated the relation between inadvertent airflow during BH and the intra-BH motion. Results: We found intra-BH tumor motion of up to 12.5 mm (range, 1.0–12.5 mm) in SI direction and up to 8.0 mm (range, 1.0–8.0 mm) in AP direction. The absolute mean motion over the patient population was 4.7 (SD: 3.0) mm and 2.8 (SD: 1.2) mm in the SI and AP direction, respectively. Patients were able to perform stable consecutive BHs; during only 20% of the movies we found very small airflows (≤ 65 ml). These were mostly stepwise in nature and could not explain the continuous tumor motions we observed. Conclusion: We found substantial (up to 12.5 mm) pancreatic tumor motion during BHs. We found minimal inadvertent airflow, seen only during a minority of BHs, and this did not explain the obtained results. This work was supported by the foundation Bergh in het Zadel through the Dutch Cancer Society (KWF Kankerbestrijding) project No. UVA 2011-5271.

  12. Pancreatic neuroendocrine tumors.

    PubMed

    Varas Lorenzo, Modesto; Cugat Andorra, Esteban; Capdevila Castillón, Jaume

    2017-06-01

    Endocrine or pancreatic neuroendocrine tumors (PNET) were first cited in the 1950s; they may be sporadic or associated with hereditary syndromes, benign or malignant, functioning or non-functioning. Nowadays, NF-PNETs are the most frequent and their prevalence ranges from 50% to 91%. In our current series (including 70 cases, 33% malignant, 52 operated) the frequency was 72% as compared to 37% in the historical series.

  13. Autoimmune pancreatitis mimicking pancreatic tumor

    PubMed Central

    Dede, Kristóf; Salamon, Ferenc; Taller, András; Teknős, Dániel; Bursics, Attila

    2012-01-01

    Autoimmune pancreatitis (AIP) is a rare disease of unknown pathomechanism. It belongs to the IgG4-related disease family and responds well to steroids, although the relapse rate can reach up to 20–30%. Differentiating AIP from the more common pancreatic cancer can be very challenging. About 20% of AIP is diagnosed postoperatively during final histological examination. Each of the investigative tools can add something to the definitive diagnosis; the question remains whether it is possible to prevent an unnecessary resection. Through our case we would like to demonstrate the differential diagnostic opportunities and present the literary background of this issue. In conclusion, we can state that whenever a focal pancreatic lesion is encountered AIP should always be considered. PMID:24968399

  14. [Pancreatic ascariasis mimicking a pancreatic tumor].

    PubMed

    Casado Maestre, María Dolores; Alamo Martínez, José María; Segura Sampedro, Juan José; Gómez Bravo, Miguel Ángel; Padillo Ruiz, Francisco Javier; Durán Izquierdo, Elena; Gavilán Carrasco, Francisco

    2011-01-01

    Ascaris lumbricoides infection in Spain is anecdotal and is usually associated with travel to areas with high endemicity such as India and South America. Biliopancreatic disease caused by this parasite is both rare and one of the most feared complications. There are few publications in the literature about pancreatic involvement in ascariasis. We describe a case of pancreatic ascariasis diagnosed after a pancreaticoduodenectomy was performed for a suspected pancreatic adenocarcinoma. A 58-year-old man consulted for longstanding abdominal pain and diarrhea. Computed tomography and magnetic resonance scans, endoscopy, and endoscopic ultrasound-guided fine-needle cytology were performed. The pathological diagnosis was moderately differentiated adenocarcinoma of the pancreatic head. Cephalic pancreaticoduodenectomy was performed. The postoperative course was favorable. A pancreatic fistula type B (ISGPF classification) developed and was resolved with conservative treatment. Analysis of the surgical specimen revealed the presence of a pancreatic pseudotumor due to Ascaris lumbricoides. After these findings, treatment was completed with oral albendazole. Pancreatic ascariasis in our environment is unusual, but should be included in the differential diagnosis of tumors and inflammatory processes of the pancreas. Copyright © 2011 Elsevier España, S.L. All rights reserved.

  15. [Pancreatic tumors: recent developments].

    PubMed

    Lariño Noia, José

    2014-09-01

    Pancreatic cancer (PC) still typically has a poor prognosis. In addition to smoking, obesity and new-onset diabetes mellitus are considered to be significant risk factors. An endoscopic ultrasound (EUS) remains the mainstay for diagnosis and on which the majority of advances are based. In this sense, needle-based confocal laser endomicroscopy (nCLE) is gaining importance in the differential diagnosis of solid pancreatic lesions and studies comparing different needle types (cytology vs. histology) for EUS-guided puncture. Intravenous contrast (IC-EUS) and elastography are additional tools associated with EUS that can assist in diagnosing PC. Regarding prognostic factors, the importance of the role of mesenteric-portal vein resection was emphasized, given the limited advances in treatment, as in previous years. Regarding cystic tumors, work focuses on validating the new international guidelines from Fukuoka 2012 (revised Sendai criteria) and on determining predictors of cystic lesion malignancy, mainly of intraductal papillary mucinous neoplasm (IPMN). From a therapeutic point of view, there are theories regarding the usefulness of alcohol and the gemcitabine-paclitaxel combination in the ablation of small mucinous cystic lesions through EUS-injection. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

  16. Pancreatic tumors imaging: An update.

    PubMed

    Scialpi, Michele; Reginelli, Alfonso; D'Andrea, Alfredo; Gravante, Sabrina; Falcone, Giuseppe; Baccari, Paolo; Manganaro, Lucia; Palumbo, Barbara; Cappabianca, Salvatore

    2016-04-01

    Currently, ultrasound (US), computed tomography (CT) and Magnetic Resonance imaging (MRI) represent the mainstay in the evaluation of pancreatic solid and cystic tumors affecting pancreas in 80-85% and 10-15% of the cases respectively. Integration of US, CT or MR imaging is essential for an accurate assessment of pancreatic parenchyma, ducts and adjacent soft tissues in order to detect and to stage the tumor, to differentiate solid from cystic lesions and to establish an appropriate treatment. The purpose of this review is to provide an overview of pancreatic tumors and the role of imaging in their diagnosis and management. In order to a prompt and accurate diagnosis and appropriate management of pancreatic lesions, it is crucial for radiologists to know the key findings of the most frequent tumors of the pancreas and the current role of imaging modalities. A multimodality approach is often helpful. If multidetector-row CT (MDCT) is the preferred initial imaging modality in patients with clinical suspicion for pancreatic cancer, multiparametric MRI provides essential information for the detection and characterization of a wide variety of pancreatic lesions and can be used as a problem-solving tool at diagnosis and during follow-up. Copyright © 2015. Published by Elsevier Ltd.

  17. Pancreatic islet cell tumor

    MedlinePlus

    ... functions. These include blood sugar level and the production of stomach acid. Tumors that arise from islet ... try and shrink the tumors. If the abnormal production of hormones is causing symptoms, you may receive ...

  18. Adaptive motion mapping in pancreatic SBRT patients using Fourier transforms.

    PubMed

    Jones, Bernard L; Schefter, Tracey; Miften, Moyed

    2015-05-01

    Recent studies suggest that 4DCT is unable to accurately measure respiratory-induced pancreatic tumor motion. In this work, we assessed the daily motion of pancreatic tumors treated with SBRT, and developed adaptive strategies to predict and account for this motion. The daily motion trajectory of pancreatic tumors during CBCT acquisition was calculated using a model which reconstructs the instantaneous 3D position in each 2D CBCT projection image. We developed a metric (termed "Spectral Coherence," SC) based on the Fourier frequency spectrum of motion in the SI direction, and analyzed the ability of SC to predict motion-based errors and classify patients according to motion characteristics. The amplitude of daily motion exceeded the predictions of pre-treatment 4DCT imaging by an average of 3.0mm, 2.3mm, and 3.5mm in the AP/LR/SI directions. SC was correlated with daily motion differences and tumor dose coverage. In a simulated adaptive protocol, target margins were adjusted based on SC, resulting in significant increases in mean target D95, D99, and minimum dose. Our Fourier-based approach differentiates between consistent and inconsistent motion characteristics of respiration and correlates with daily motion deviations from pre-treatment 4DCT. The feasibility of an SC-based adaptive protocol was demonstrated, and this patient-specific respiratory information was used to improve target dosimetry by expanding coverage in inconsistent breathers while shrinking treatment volumes in consistent breathers. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. Adaptive motion mapping in pancreatic SBRT patients using Fourier transforms

    PubMed Central

    Jones, Bernard L.; Schefter, Tracey; Miften, Moyed

    2015-01-01

    Background and Purpose Recent studies suggest that 4DCT is unable to accurately measure respiratory-induced pancreatic tumor motion. In this work, we assessed the daily motion of pancreatic tumors treated with SBRT, and developed adaptive strategies to predict and account for this motion. Materials and Methods The daily motion trajectory of pancreatic tumors during CBCT acquisition was calculated using a model which reconstructs the instantaneous 3D position in each 2D CBCT projection image. We developed a metric (termed “Spectral Coherence,” SC) based on the Fourier frequency spectrum of motion in the SI direction, and analyzed the ability of SC to predict motion-based errors and classify patients according to motion characteristics. Results The amplitude of daily motion exceeded the predictions of pre-treatment 4DCT imaging by an average of 3.0 mm, 2.3 mm, and 3.5 mm in the AP/LR/SI directions. SC was correlated with daily motion differences and tumor dose coverage. In a simulated adaptive protocol, target margins were adjusted based on SC, resulting in significant increases in mean target D95, D99, and minimum dose. Conclusions Our Fourier-based approach differentiates between consistent and inconsistent motion characteristics of respiration and correlates with daily motion deviations from pre-treatment 4DCT. The feasibility of an SC-based adaptive protocol was demonstrated, and this patient-specific respiratory information was used to improve target dosimetry by expanding coverage in inconsistent breathers while shrinking treatment volumes in consistent breathers. PMID:25890573

  20. Pancreatic endocrine tumors.

    PubMed

    Asa, Sylvia L

    2011-04-01

    The endocrine cells of the pancreas and their related cells throughout the gastrointestinal tract give rise to a variety of tumors that pose a diagnostic challenge. There has been progress in understanding their histogenesis, morphology, immunohistochemistry, molecular biology and classifications. This review will focus on nomenclature/terminology, classification, the role of immunohistochemistry, molecular advances, including genetic predisposition, and potential therapeutic targets to define the role of pathology in the application of prognostic and predictive markers for this disease.

  1. Diagnosis of pancreatic tumors by endoscopic ultrasonography

    PubMed Central

    Sakamoto, Hiroki; Kitano, Masayuki; Kamata, Ken; El-Masry, Muhammad; Kudo, Masatoshi

    2010-01-01

    Pancreatic tumors are highly diverse, as they can be solid or cystic, and benign or malignant. Since their imaging features overlap considerably, it is often difficult to characterize these tumors. In addition, small pancreatic tumors, especially those less than 2 cm in diameter, are difficult to detect and diagnose. For characterizing pancreatic tumors and detecting small pancreatic tumors, endoscopic ultrasonography (EUS) is the most sensitive of the imaging procedures currently available. This technique also provides good results in terms of the preoperative staging of pancreatic tumors. EUS-guided fine needle aspiration (EUS-FNA) has also proved to be a safe and useful method for tissue sampling of pancreatic tumors. Despite these advantages, however, it is still difficult to differentiate between benign and malignant, solid or cystic pancreatic tumors, malignant neoplasms, and chronic pancreatitis using EUS, even when EUS-FNA is performed. Recently, contrast-enhanced EUS with Doppler mode (CE-EUS) employing ultrasound contrast agents, which indicate vascularization in pancreatic lesions, has been found to be useful in the differential diagnosis of pancreatic tumors, especially small pancreatic tumors. However, Doppler ultrasonography with contrast-enhancement has several limitations, including blooming artifacts, poor spatial resolution, and low sensitivity to slow flow. Consequently, an echoendoscope was developed recently that has a broad-band transducer and an imaging mode that was designed specifically for contrast-enhanced harmonic EUS (CEH-EUS) with a second-generation ultrasound contrast agent. The CEH-EUS technique is expected to improve the differential diagnosis of pancreatic disease in the future. This review describes the EUS appearances of common solid and cystic pancreatic masses, the diagnostic accuracy of EUS-FNA, and the relative efficacies and advantages of CE-EUS and CEH-EUS along with their relative advantages and their complementary roles

  2. Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors

    PubMed Central

    Metz, David C.

    2008-01-01

    Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending upon whether the tumor is functional or not and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging and monitoring. Initially, therapy should be directed at the hormonal syndrome as this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas which are predominantly benign. Surgery is the only modality that offers the possibility of cure although it is generally noncurative in patients with Zollinger-Ellison syndrome or nonfunctional PETs with MEN1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection though debulking surgery is often felt to be useful in unresectable patients. Once metastatic, biotherapy is usually the first modality employed because it is generally well tolerated. Systemic or regional therapies are generally reserved until symptoms occur or tumor growth is rapid. Recently a number of newer agents, as well as receptor-directed radiotherapy, are being evalulated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization and management of PETs including discussion of peptide receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field. PMID:18703061

  3. Systemic Therapies for Advanced Pancreatic Neuroendocrine Tumors

    PubMed Central

    Raj, Nitya; Reidy-Lagunes, Diane

    2016-01-01

    SYNOPSIS Pancreatic neuroendocrine tumors are a rare tumor type, and comprise 1-2% of all pancreatic neoplasms. When nonfunctional (i.e. nonhormone secreting), these tumors generally cause few symptoms and often go unnoticed for several years; for this reason, they are rarely localized at presentation, and are typically diagnosed in the presence of metastatic disease, most commonly to the liver. Although pancreatic neuroendocrine tumors can be less aggressive than other tumor types, the management poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The therapy of pancreatic neuroendocrine tumors includes a multimodality approach and can often include surgery, liver-directed therapies (i.e. embolization), as well as targeted and cytotoxic systemic treatments. A variety of systemic therapies have been developed for the management of pancreatic neuroendocrine tumors. These therapies include somatostatin analogs (octreotide or lanreotide), a select group of cytotoxic chemotherapy agents (alkylating, fluorouracil and platinum drugs), as well as targeted or biologic agents (everolimus and sunitinib). This chapter will review the available systemic therapy options for advanced pancreatic neuroendocrine tumors. PMID:26614372

  4. Radiotherapy for Pancreatic Neuroendocrine Tumors

    SciTech Connect

    Contessa, Joseph N.; Griffith, Kent A.; Wolff, Elizabeth; Ensminger, William; Zalupski, Mark; Ben-Josef, Edgar

    2009-11-15

    Purpose: Pancreatic neuroendocrine tumors (PNTs) are rare malignant neoplasms considered to be resistant to radiotherapy (RT), although data on efficacy are scarce. We reviewed our institutional experience to further delineate the role of RT for patients with PNTs. Methods and Materials: Between 1986 and 2006, 36 patients with PNTs were treated with RT to 49 sites. Of these 36 patients, 23 had radiographic follow-up data, which were used to determine the tumor response rate and freedom from local progression. Long-term toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: The overall response rate to RT was 39% (13% complete response, 26% partial response, 56% stable disease, and 4% progressive disease). A significant difference in the freedom from local progression between the groups receiving either greater than or less than the median 2 Gy/fraction biologically equivalent dose of 49.6 Gy was found, with all radiographic progression occurring in patients who had received <=32 Gy. The actuarial 3-year local freedom from progression rate was 49%. Palliation was achieved in 90% of patients, with either improvement or resolution of symptoms after RT. Of 35 patients, 33 had metastatic disease at their referral for RT, and the median overall survival for this patient population was 2 years. Three long-term Grade 3 or greater toxicities were recorded. Conclusion: RT is an effective modality for achieving local control in patients with PNTs. RT produces high rates of symptomatic palliation and freedom from local progression. Prospective trials of radiotherapy for PNTs are warranted.

  5. Capecitabine, Temozolomide and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2016-09-21

    Gastrinoma; Glucagonoma; Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Islet Cell Carcinoma; Recurrent Pancreatic Cancer; Somatostatinoma; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer

  6. Tumor antigens as related to pancreatic cancer.

    PubMed

    Chu, T M; Holyoke, E D; Douglass, H O

    1980-01-01

    Data are presented suggesting the presence of pancreas tumor-associated antigens. Slow progress has been made during the past few years in the identification of pancreatic tumor antigens that may be of clinical usefulness and it seems unlikely that many of the practical problems now being faced in identification and isolation of these antigens and in development of a specific, sensitive assay will be solved by conventional immunochemical approaches. The study of antigen and/or antibody purified from immune complexes in the host and the application of leukocyte adherence inhibition techniques to immunodiagnosis of pancreatic cancer are among the new approaches that may provide effective alternatives in the study of pancreatic tumor antigens.

  7. Pancreatic endocrine neoplasms: Epidemiology and prognosis of pancreatic endocrine tumors

    PubMed Central

    Halfdanarson, Thorvardur R.; Rubin, Joseph; Farnell, Michael B.; Grant, Clive S.; Petersen, Gloria M.

    2009-01-01

    Pancreatic endocrine neoplasms (PETs) are uncommon tumors with an annual incidence less than 1 per 100,000 persons per year in the general population. PETs that produce hormones resulting in symptoms are designated as functional. The majority of PETs are nonfunctional. Of the functional tumors, insulinomas are the most common, followed by gastrinomas. The clinical course of patients with PETs is variable and depends on the extent of the disease and the treatment rendered. Patients with completely resected tumors generally have a good prognosis, and aggressive surgical therapy in patients with advanced disease may also prolong survival. The epidemiology, prognosis and established and novel prognostic markers of PETs are reviewed. PMID:18508996

  8. The Yolk Sac Feeds Pancreatic Tumors.

    PubMed

    Pollard, Jeffrey W

    2017-08-15

    In this issue of Immunity, Zhu et al. (2017) report that tumor-associated macrophages in a mouse model of pancreatic ductal adenocarcinoma (PDAC) originate from both the yolk sac (YS) and bone marrow. Differential ablation of these populations indicates that only the YS-derived macrophages promote PDAC progression and growth. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. [DIAGNOSIS OF VASCULAR INVASION BY PANCREATIC TUMORS].

    PubMed

    Dronov, O I; Zemskov, S V; Bakunets, P P

    2016-02-01

    Basing on analysis of own material (84 patients) and data of literature there was established, that vascular invasion by pancreatic tumors constitutes the main obstacle for conduction of the patients' radical treatment. Early diagnosis permits radical resectability of the patients, what constitutes the only one effective method of treatment. In vascular invasion by tumor a surgeon experience and professional preparation determines possibility of the extended operation performance with intervention on affected main vessel, enhancing the treatment radicalism.

  10. Pancreatic tumor of mesenchymal origin--an unusual surgical finding.

    PubMed

    Peskova, M; Fried, M

    1994-04-01

    Recently, a patient with an unusual pancreatic tumor of smooth muscle origin, presented at the First Surgical Clinic, Charles University Hospital, Prague. Leiomyosarcoma, a malignant smooth muscle tumor, may arise almost anywhere in the body. Pancreatic localization is very unusual. A number of authors have surveyed the literature on pancreatic tumors of mesenchymal origin. As many as fifty cases have been reported in autopsy studies since 1882. Only six operated cases of pancreatic sarcomas were found in surgical series.

  11. Radiological description of cystic pancreatic tumors.

    PubMed

    Rodríguez Torres, C; Larrosa López, R

    2016-01-01

    Although most cystic pancreatic lesions are pseudocysts, it is important to do a thorough differential diagnosis with true cystic tumors because cystic tumors are potentially malignant. Sometimes computed tomography and magnetic resonance imaging cannot establish the definitive diagnosis, making it necessary to perform other imaging tests such as endoscopic ultrasound, which in addition to morphological information, can also enable cytologic and biochemical analysis of the lesion through puncture and aspiration of its contents. Combining all these findings nearly always provides enough diagnostic information to allow the appropriate approach in each case. This article describes the specific morphological characteristics for each cystic pancreatic tumor on computed tomography, magnetic resonance imaging, and endoscopic ultrasound and reviews the guidelines for managing these types of lesions.

  12. Pancreatic neuroendocrine tumors: biology, diagnosis, and treatment

    PubMed Central

    Ro, Cynthia; Chai, Wanxing; Yu, Victoria E.; Yu, Run

    2013-01-01

    Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of familial and sporadic PNETs are somewhat understood, but their molecular pathogenesis remains unknown. Most PNETs are indolent but have malignant potential. The biological behavior of an individual PNET is unpredictable; higher tumor grade, lymph node and liver metastasis, and larger tumor size generally indicate a less favorable prognosis. Endocrine testing, imaging, and histological evidence are necessary to accurately diagnose PNETs. A 4-pronged aggressive treatment approach consisting of surgery, locoregional therapy, systemic therapy, and complication control has become popular in academic centers around the world. The optimal application of the multiple systemic therapeutic modalities is under development; efficacy, safety, availability, and cost should be considered when treating a specific patient. The clinical presentation, diagnosis, and treatment of specific types of PNETs and familial PNET syndromes, including the novel Mahvash disease, are summarized. PMID:23237225

  13. Intravital characterization of tumor cell migration in pancreatic cancer

    PubMed Central

    Beerling, Evelyne; Oosterom, Ilse; Voest, Emile; Lolkema, Martijn; van Rheenen, Jacco

    2016-01-01

    ABSTRACT Curing pancreatic cancer is difficult as metastases often determine the poor clinical outcome. To gain more insight into the metastatic behavior of pancreatic cancer cells, we characterized migratory cells in primary pancreatic tumors using intravital microscopy. We visualized the migratory behavior of primary tumor cells of a genetically engineered pancreatic cancer mouse model and found that pancreatic tumor cells migrate with a mesenchymal morphology as single individual cells or collectively as a stream of non-cohesive single motile cells. These findings may improve our ability to conceive treatments that block metastatic behavior. PMID:28243522

  14. A retroperitoneal neuroendocrine tumor in ectopic pancreatic tissue.

    PubMed

    Okasha, Hussein Hassan; Al-Bassiouni, Fahim; El-Ela, Monir Abo; Al-Gemeie, Emad Hamza; Ezzat, Reem

    2013-07-01

    Ectopic pancreas is the relatively uncommon presence of pancreatic tissue outside the normal location of the pancreas. We report a case of abdominal pain due to retroperitoneal neuroendocrine tumor arising from heterotopic pancreatic tissue between the duodenal wall and the head of the pancreas. Patient underwent surgical enucleation of the tumor.

  15. Pancreatic neuroendocrine tumors: does chemotherapy work?

    PubMed

    Tejani, Mohamedtaki Abdulaziz; Saif, Muhammad Wasif

    2014-03-10

    Pancreatic neuroendocrine tumors (pNETs) are rare well-differentiated neoplasms which can be functional or non-functional. They tend to have a worse prognosis than their counterpart carcinoid tumors. Current systemic treatment options for advanced, unresectable disease include somatostatin analogs, everolimus and sunitinib. Low response rates and toxicity profiles have, thus far, limited the widespread use of cytotoxic chemotherapy in this setting. In this update, we review three abstracts from the 2014 ASCO Gastrointestinal Cancers Symposium that present outcomes of the use of combination capecitabine and temozolomide in patients with advanced pNET. We summarize their results and discuss the role of this regimen in treatment algorithms for metastatic pNET.

  16. Current medical treatment of pancreatic neuroendocrine tumors.

    PubMed

    Yalcin, Suayib; Oyan, Basak; Bayraktar, Yusuf

    2007-01-01

    Pancreatic neuroendocrine tumors (NETs) consist of a wide group of neoplasms, with different biological behaviors in terms of aggressiveness and hormone production. In the last two decades, significant progress has been observed in our understanding of their biology, diagnosis and treatment. Surgery remains to be the only curative approach, but unfortunately the diagnosis is often delayed due to the slow growth of these tumors and the difficulty in identifying the symptoms related to the tumor-released hormones. In addition to surgery, other approaches to control the disease are biological therapy consisting of somatostatin analogs and interferon (IFN), systemic chemotherapy, radioligand therapy and local therapy with chemoembolization. Several newer cytotoxic agents, including irinotecan, gemcitabine, taxanes, oxaliplatin, capecitabine and PS-341 have been studied in metastatic patients. Considering the high vascularity of these tumors, antiangiogenic agents like endostatin and thalidomide have also been evaluated in advanced NETs. Although these agents seem to have potential activity in NETs and may increase progression free survival, none of these currently available medical therapeutic options are curative. While more efficient novel strategies are to be developed, the rationale use of the current therapeutic options may improve quality of life, control the symptoms related to the hypersecretion of hormones and/or peptides, control tumor proliferation and prolong survival in patients suffering from NETs.

  17. An evaluation of motion mitigation techniques for pancreatic SBRT.

    PubMed

    Campbell, Warren G; Jones, Bernard L; Schefter, Tracey; Goodman, Karyn A; Miften, Moyed

    2017-07-01

    Ablative radiation therapy can be beneficial for pancreatic cancer, and motion mitigation helps to reduce dose to nearby organs-at-risk. Here, we compared two competing methods of motion mitigation-abdominal compression and respiratory gating. CBCT scans of 19 pancreatic cancer patients receiving stereotactic body radiation therapy were acquired with and without abdominal compression, and 3D target motion was reconstructed from CBCT projection images. Daily target motion without mitigation was compared against motion with compression and with simulated respiratory gating. Gating was free-breathing and based on an external surrogate. Target coverage was also evaluated for each scenario by simulating reduced target margins. Without mitigation, average daily target motion in LR/AP/SI directions was 5.3, 7.3, and 13.9mm, respectively. With abdominal compression, these values were 5.2, 5.3, and 8.5mm, and with respiratory gating they were 3.2, 3.9, and 5.5mm, respectively. Reductions with compression were significant in AP/SI directions, while reductions with gating were significant in all directions. Respiratory gating also demonstrated better coverage in the reduced margins scenario. Respiratory gating is the most effective strategy for reducing motion in pancreatic SBRT, and may allow for dose escalation through a reduction in target margin. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Collision tumors: pancreatic adenocarcinoma and mantle cell lymphoma.

    PubMed

    Dasanu, Constantin A; Shimanovsky, Alexei; Rotundo, Edyta K; Posteraro, Anthony F; Cooper, Dennis L; Atienza, Jonessa A

    2013-07-10

    Collision tumors are very rare entities composed of two or more distinct tumor components, each separated by normal tissue. Perhaps due to technical advances in the last decade, the incidence of collision tumors has been on the rise. To the best of our knowledge, collision tumors featuring mantle cell lymphoma and pancreatic adenocarcinoma have not been previously described in the scientific literature. For the first time, we describe herein the clinical course of a collision tumor between pancreatic adenocarcinoma and mantle cell lymphoma. We hypothesize several aspects in the pathogenesis of a such event and review the existing literature on collision tumors.

  19. Targeted Therapies Improve Survival for Patients with Pancreatic Neuroendocrine Tumors

    Cancer.gov

    In 2011, based on initial findings from two clinical trials, the Food and Drug Administration approved sunitinib and everolimus for patients with pancreatic neuroendocrine tumors. Updated results from the everolimus trial were published in September 2016.

  20. Immunohistochemical study of pancreatic neuroendocrine tumor in Panthera tigris tigris.

    PubMed

    Nyska, A; Goldstein, J; Eshkar, G; Klein, B

    1996-07-01

    The histological and immunohistochemical characteristics of a case of pancreatic neuroendocrine tumor are described in a 14-yr-old female Bengal tiger (Panthera tigris tigris) housed at the New Biblical Zoo of Jerusalem, Jerusalem, Israel, 1994. The neoplastic cells were immunohistochemically negative for insulin and glucagon, slightly positive for neuron-specific enolase, moderately positive for serotonin and somatostatin, and markedly positive for chromogranine A and gastrin. This is the first documentation of a pancreatic neuroendocrine tumor in the tiger.

  1. Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma

    PubMed Central

    Neesse, Albrecht; Krug, Sebastian; Gress, Thomas M; Tuveson, David A; Michl, Patrick

    2014-01-01

    Pancreatic ductal adenocarcinoma is a stroma-rich and highly challenging cancer to treat. Over recent years, it has become increasingly evident that the complex network of soluble cytokines, growth factors, proteases, and components of the extracellular matrix collaboratively interact within the tumor microenvironment, sustaining and driving cancer cell proliferation, invasion, and early metastasis. More recently, the tumor microenvironment has also been appreciated to mediate therapeutic resistance in pancreatic ductal adenocarcinoma, thus opening numerous avenues for novel therapeutic explorations. Inert and soluble components of the tumor stroma have been targeted in order to break down the extracellular matrix scaffold, relieve vessel compression, and increase drug delivery to hypovascular tumors. Moreover, targeting of antiapoptotic, immunosuppressive, and pro-proliferative effects of the tumor stroma provides novel vantage points of attack. This review focuses on current and future developments in pancreatic cancer medicine, with a particular emphasis on biophysical and biochemical approaches that target the tumor microenvironment. PMID:24379681

  2. Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion?

    SciTech Connect

    Yang, Juan; Cai, Jing; Wang, Hongjun; Chang, Zheng; Czito, Brian G.; Bashir, Mustafa R.; Palta, Manisha; Yin, Fang-Fang

    2014-11-15

    Purpose: To evaluate the relationship between liver tumor motion and diaphragm motion. Methods and Materials: Fourteen patients with hepatocellular carcinoma (10 of 14) or liver metastases (4 of 14) undergoing radiation therapy were included in this study. All patients underwent single-slice cine–magnetic resonance imaging simulations across the center of the tumor in 3 orthogonal planes. Tumor and diaphragm motion trajectories in the superior–inferior (SI), anterior–posterior (AP), and medial–lateral (ML) directions were obtained using an in-house-developed normalized cross-correlation–based tracking technique. Agreement between the tumor and diaphragm motion was assessed by calculating phase difference percentage, intraclass correlation coefficient, and Bland-Altman analysis (Diff). The distance between the tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between the 2 motions. Results: Of all patients, the mean (±standard deviation) phase difference percentage values were 7.1% ± 1.1%, 4.5% ± 0.5%, and 17.5% ± 4.5% in the SI, AP, and ML directions, respectively. The mean intraclass correlation coefficient values were 0.98 ± 0.02, 0.97 ± 0.02, and 0.08 ± 0.06 in the SI, AP, and ML directions, respectively. The mean Diff values were 2.8 ± 1.4 mm, 2.4 ± 1.1 mm, and 2.2 ± 0.5 mm in the SI, AP, and ML directions, respectively. Tumor and diaphragm motions had high concordance when the distance between the tumor and tracked diaphragm area was small. Conclusions: This study showed that liver tumor motion had good correlation with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be used as a reliable surrogate for liver tumor motion.

  3. Targeting pancreatic expressed PAX genes for the treatment of diabetes mellitus and pancreatic neuroendocrine tumors.

    PubMed

    Martin-Montalvo, Alejandro; Lorenzo, Petra I; López-Noriega, Livia; Gauthier, Benoit R

    2017-01-01

    Four members of the PAX family, PAX2, PAX4, PAX6 and PAX8 are known to be expressed in the pancreas. Accumulated evidences indicate that several pancreatic expressed PAX genes play a significant role in pancreatic development/functionality and alterations in these genes are involved in the pathogenesis of pancreatic diseases. Areas covered: In this review, we summarize the ongoing research related to pancreatic PAX genes in diabetes mellitus and pancreatic neuroendocrine tumors. We dissect the current knowledge at different levels; from mechanistic studies in cell lines performed to understand the molecular processes controlled by pancreatic PAX genes, to in vivo studies using rodent models that over-express or lack specific PAX genes. Finally, we describe human studies associating variants on pancreatic-expressed PAX genes with pancreatic diseases. Expert opinion: Based on the current literature, we propose that future interventions to treat pancreatic neuroendocrine tumors and diabetes mellitus could be developed via the modulation of PAX4 and/or PAX6 regulated pathways.

  4. Analysis of clinical characteristics and treatment of pancreatic cystic tumors

    PubMed Central

    You, Lei; Xiao, Jianchun; Cao, Zhe; Zhang, Wanying; Liao, Quan; Dai, Menghua; Zhang, Taiping; Zhao, Yupei

    2016-01-01

    Objective To summarize experience in the diagnosis and treatment of pancreatic cystic neoplasms. Methods This is a retrospective study of 207 patients who were diagnosed with pancreatic cystic tumors at Peking Union Medical College Hospital between Jan 2009 and Mar 2014. Clinical data, such as clinical manifestations, radiological and pathological images and surgical recordings, were collected. Results Of the 207 included patients, females accounted for 76.81%, and the mean patient age was 52.04 years. Malignancy was more common in older patients who presented with marasmus and jaundice. Other risk factors included solid components in the tumor, a large tumor size, and elevated levels of tumor markers. Surgical treatment was required when a malignant tumor was suspected. The operation approach was selected based on the location, size and characteristics of the tumor. The position of the tumor relative to the pancreatic duct also played a significant role. Conclusions No specific symptoms were observed for the patients with pancreatic cystic tumors. Imaging played an important role in making a differential diagnosis. Furthermore, surgical treatment should be proposed for patients with significant symptoms and potentially malignant tumors. The tumor resection rate is high, suggestive of good prognosis. PMID:27877011

  5. Penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis

    PubMed Central

    Ranjan, Alok; Srivastava, Sanjay K.

    2016-01-01

    Pancreatic tumors exhibit enhanced autophagy as compared to any other cancer, making it resistant to chemotherapy. We evaluated the effect of penfluridol against pancreatic cancer. Penfluridol treatment induced apoptosis and inhibited the growth of Panc-1, BxPC-3 and AsPC-1, pancreatic cancer cells with IC50 ranging between 6–7 μM after 24 h of treatment. Significant autophagy was induced by penfluridol treatment in pancreatic cancer cells. Punctate LC3B and autophagosomes staining confirmed autophagy. Inhibiting autophagy by chloroquine, bafilomycin, 3-methyladenine or LC3BsiRNA, significantly blocked penfluridol-induced apoptosis, suggesting that autophagy lead to apoptosis in our model. Penfluridol treatment suppressed the growth of BxPC-3 tumor xenografts by 48% as compared to 17% when treated in combination with chloroquine. Similarly, penfluridol suppressed the growth of AsPC-1 tumors by 40% versus 16% when given in combination with chloroquine. TUNEL staining and caspase-3 cleavage revealed less apoptosis in the tumors from mice treated with penfluridol and chloroquine as compared to penfluridol alone. Penfluridol treatment also suppressed the growth of orthotopically implanted Panc-1 tumors by 80% by inducing autophagy-mediated apoptosis in the tumors. These studies established that penfluridol inhibits pancreatic tumor growth by autophagy-mediated apoptosis. Since penfluridol is already in clinic, positive findings from our study will accelerate its clinical development. PMID:27189859

  6. Alisertib and Gemcitabine Hydrochloride in Treating Patients With Solid Tumors or Pancreatic Cancer

    ClinicalTrials.gov

    2017-01-19

    Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Recurrent Pancreatic Cancer; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  7. Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors.

    PubMed

    Hall, MacLean; Liu, Hao; Malafa, Mokenge; Centeno, Barbara; Hodul, Pamela J; Pimiento, José; Pilon-Thomas, Shari; Sarnaik, Amod A

    2016-01-01

    We evaluated whether tumor infiltrating lymphocytes (TIL) could be expanded from surgically resected tumors from pancreatic cancer patients. Tumors were resected from pancreatic cancer patients. Tumors were minced into fragments and cultured in media containing high dose interleukin-2 (IL-2) for up to 6 weeks. T cell phenotype, activation markers, and reactivity were measured. TIL expansion was measured in 19 patient samples. The majority of these TIL were CD4(+) T cells and were highly activated. Purified CD8(+) T cells produced IFN-γ in response to HLA-matched pancreatic tumor targets. PD-1 blockade and 4-1BB stimulation were demonstrated as effective strategies to improve effective TIL yield, including the production of tumor-reactive pancreatic TIL. TIL expanded from pancreatic tumors are functional and able to respond to pancreatic tumor associated antigens. PD-1 blockade, 41BB stimulation, and CD8(+) T cell enrichment are effective strategies to improve TIL yield and tumor reactivity. These results support the development of adoptive cell therapy strategies using TIL for the treatment of pancreatic cancer.

  8. Targeting pancreatitis blocks tumor-initiating stem cells and pancreatic cancer progression

    PubMed Central

    Madka, Venkateshwar; Brewer, Misty; Ritchie, Rebekah L.; Lightfoot, Stan; Kumar, Gaurav; Sadeghi, Michael; Patlolla, Jagan Mohan R.; Yamada, Hiroshi Y.; Cruz-Monserrate, Zobeida; May, Randal; Houchen, Courtney W.; Steele, Vernon E.; Rao, Chinthalapally V.

    2015-01-01

    Recent development of genetically engineered mouse models (GEMs) for pancreatic cancer (PC) that recapitulates human disease progression has helped to identify new strategies to delay/inhibit PC development. We first found that expression of the pancreatic tumor-initiating/cancer stem cells (CSC) marker DclK1 occurs in early stage PC and in both early and late pancreatic intraepithelial neoplasia (PanIN) and that it increases as disease progresses in GEM and also in human PC. Genome-wide next generation sequencing of pancreatic ductal adenocarcinoma (PDAC) from GEM mice revealed significantly increased DclK1 along with inflammatory genes. Genetic ablation of cyclo-oxygenase-2 (COX-2) decreased DclK1 in GEM. Induction of inflammation/pancreatitis with cerulein in GEM mice increased DclK1, and the novel dual COX/5-lipoxygenase (5-LOX) inhibitor licofelone reduced it. Dietary licofelone significantly inhibited the incidence of PDAC and carcinoma in situ with significant inhibition of pancreatic CSCs. Licofelone suppressed pancreatic tumor COX-2 and 5-LOX activities and modulated miRNAs characteristic of CSC and inflammation in correlation with PDAC inhibition. These results offer a preclinical proof of concept to target the inflammation initiation to inhibit cancer stem cells early for improving the treatment of pancreatic cancers, with immediate clinical implications for repositioning dual COX/5-LOX inhibitors in human trials for high risk patients. PMID:25906749

  9. [Neuroendocrine pancreatic tumors and helpfulness of targeted therapies].

    PubMed

    Vaysse, Thibaut; Coriat, Romain; Perkins, Géraldine; Dhooge, Marion; Brezault, Catherine; Chaussade, Stanislas

    2013-06-01

    The neuroendocrine pancreatic tumors are rare tumors, but their incidence is constantly rising. Even if the management of these tumors has to be surgical as soon as possible, the disease is most often metastatic at the stage of the diagnostic. The prognostic and the therapeutic options differ from pancreatic adenocarcinoma. Available treatments have evolved over the last years with recent publications of studies that bring to light the benefits of targeted therapies in this pathology. This has resulted in modifications of both practices and either French and international guidelines. Therefore, we focus on the management of the grade 1 and grade 2 well-differentiated neuroendocrine pancreatic tumors as classified in new WHO classification of neuroendocrine neoplasms published in 2010.

  10. CHIP is a novel tumor suppressor in pancreatic cancer and inhibits tumor growth through targeting EGFR

    PubMed Central

    Wang, Tianxiao; Yang, Jingxuan; Xu, Jianwei; Li, Jian; Cao, Zhe; Zhou, Li; You, Lei; Shu, Hong; Lu, Zhaohui; Li, Huihua; Li, Min; Zhang, Taiping; Zhao, Yupei

    2014-01-01

    Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathways. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo. The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer. PMID:24722501

  11. Pancreatic solid cystic desmoid tumor: case report and literature review.

    PubMed

    Xu, Bin; Zhu, Ling-Hua; Wu, Jia-Guo; Wang, Xian-Fa; Matro, Erik; Ni, Jun-Jun

    2013-12-14

    Desmoid tumors (DTs) are nonmetastatic, locally aggressive neoplasms with a high rate of postoperative recurrence. Pancreatic DTs are especially rare; only a few cases have been reported to date. This paper describes a case of a sporadic cystic DT of the pancreas managed successfully with central pancreatectomy, with no signs of recurrence 40 mo after surgery. According to the literature, this is the first reported case in China of a pancreatic DT presenting as a solid cystic lesion, as well as the first pancreatic DT managed with central pancreatectomy and pancreaticogastrostomy. We report the case for its rarity and emphasize disease management by concerted application of clinical, pathological, radiological and immunohistochemical analyses.

  12. Heterotopic Pancreatic Pseudocyst Radiologically Mimicking Gastrointestinal Stromal Tumor

    PubMed Central

    Sarsenov, Dauren; Tırnaksız, Mehmet Bülent; Doğrul, Ahmet Bülent; Tanas, Özlem; Gedikoglu, Gökhan; Abbasoğlu, Osman

    2015-01-01

    Heterotopic pancreas is a relatively common variant of foregut embryologic dystopia that can be described as pancreatic tissue found outside the normal anatomic location, being independent from vascular supply of normal pancreas. Having all features of pancreatic tissue except for the major duct structures, this ectopic tissue may be clinically recognized when pathologic changes take place. Inflammation, hemorrhagic or obstructive states, and eventually malignancy-related problems may become a diagnostic challenge for clinician and finally lead to consequences of misdiagnosis. In this article we will discuss a case of heterotopic pancreatic tissue located in gastric cardia, which was diagnosed preoperatively as gastrointestinal stromal tumor. PMID:25785332

  13. Pancreatic neuroendocrine tumors in twelve baboons (Papio spp.).

    PubMed

    Owston, M A; LaRue, M K; Dick, E J; Ambrus, A; Porter, B F

    2016-04-01

    Pancreatic neuroendocrine tumors (PNETs) are rare in nonhuman primates and in humans. Twenty-one PNETs from twelve female baboons (Papio spp.) from the Southwest National Primate Research Center were evaluated using histopathology and immunohistochemistry. Histologically, all tumors were benign and had neuroendocrine packeting. Immunohistochemical staining for synaptophysin and chromogranin was positive in all tumors evaluated (17/17). Insulin was positive in 16 of 21 tumors. Somatostatin was positive in 9 of 20 tumors. Multifocal staining for glucagon and pancreatic polypeptide was evident in a minority of tumors (6/20 and 2/17, respectively). Gastrin and vasoactive intestinal peptide were negative in all tumors evaluated. Nine tumors expressed more than one hormone marker. This is the first detailed pathologic study of pancreatic endocrine tumors in the baboon. The findings suggest that these tumors are generally benign and have similar morphologic and immunohistochemical features as those described in people, including the ability to express multiple hormones. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Pancreatic Neuroendocrine Tumors in Twelve Baboons (Papio spp.)

    PubMed Central

    Owston, M.A.; LaRue, M.K.; Dick, E.J.; Ambrus, A.; Porter, B.F.

    2016-01-01

    Background Pancreatic neuroendocrine tumors (PNETs) are rare in nonhuman primates and in humans. Methods Twenty-one PNETs from twelve female baboons (Papio spp.) from the Southwest National Primate Research Center were evaluated using histopathology and immunohistochemistry. Results Histologically, all tumors were benign and had neuroendocrine packeting. Immunohistochemical staining for synaptophysin and chromogranin was positive in all tumors evaluated (17/17). Insulin was positive in 16/21 tumors. Somatostatin was positive in 9/20 tumors. Multifocal staining for glucagon and pancreatic polypeptide was evident in a minority of tumors (6/20 and 2/17, respectively). Gastrin and vasoactive intestinal peptide were negative in all tumors evaluated. Nine tumors expressed more than one hormone marker. Conclusions This is the first detailed pathologic study of pancreatic endocrine tumors in the baboon. The findings suggest that these tumors are generally benign and have similar morphologic and immunohistochemical features as those described in people, including the ability to express multiple hormones. PMID:26899153

  15. Pancreatic solitary fibrous tumor causing ectopic adrenocorticotropic hormone syndrome.

    PubMed

    Murakami, Keigo; Nakamura, Yasuhiro; Felizola, Saulo J A; Morimoto, Ryo; Satoh, Fumitoshi; Takanami, Kentaro; Katakami, Hideki; Hirota, Seiichi; Takeda, Yoshiyu; Meguro-Horike, Makiko; Horike, Shin-Ichi; Unno, Michiaki; Sasano, Hironobu

    2016-11-15

    Solitary fibrous tumors occasionally present with hypoglycemia because of the excessive release of insulin-like growth factor II. We report the first case of pancreatic solitary fibrous tumor causing ectopic adrenocorticotropic hormone syndrome. An 82-year-old Japanese man presented with lower limb edema, uncontrolled hypertension, hypokalemia, and baseline hypercortisolism. Distal pancreatectomy was performed after the clinical diagnosis of a neuroendocrine tumor with ectopic secretion of adrenocorticotropic hormone. On histological examination, the tumor showed spindle cells in a fascicular arrangement. The diagnosis of the solitary fibrous tumor was confirmed by the identification of the NAB2-STAT6 fusion gene and positive immuno-histochemical staining for STAT6 and CD34. Using quantitative real-time polymerase chain reaction, mRNA that encoded proopiomelanocortin, precursor of adrenocorticotropic hormone, was detected. Proopiomelanocortin production through the demethylation of the promoter region Domain IV was detected. Pancreatic solitary fibrous tumors represent a new cause of ectopic adrenocorticotropic hormone syndrome.

  16. Intraoperative methods to stage and localize pancreatic and duodenal tumors.

    PubMed

    Norton, J A

    1999-01-01

    Intraoperative methods to stage and localize tumors have dramatically improved. Advances include less invasive methods to obtain comparable results and precise localization of previously occult tumors. The use of new technology including laparoscopy and ultrasound has provided some of these advances, while improved operative techniques have provided others. Laparoscopy with ultrasound has allowed for improved staging of patients with pancreatic cancer and exclusion of patients who are not resectable for cure. We performed laparoscopy with ultrasound on 50 consecutive patients with adenocarcinoma of the pancreas or liver who appeared to have resectable tumors based on preoperative computed tomography. 22 patients (44%) were found to be unresectable because of tumor nodules on the liver and/or peritoneal surfaces or unsuspected distant nodal or liver metastases. The site of disease making the patient unresectable was confirmed by biopsy in each case. Of the 28 remaining patients in whom laparoscopic ultrasound predicted to be resectable for cure, 26 (93%) had all tumor removed. Thus laparoscopy with ultrasound was the best method to select patients for curative surgery. Intraoperative ultrasound (IOUS) has been a critical method to identify insulinomas that are not palpable. Nonpalpable tumors are most commonly in the pancreatic head. Because the pancreatic head is thick and insulinomas are small, of 9 pancreatic head insulinomas only 3 (33%) were palpable. However, IOUS precisely identified each (100%). Others have recommended blind distal pancreatectomy for individuals with insulinoma in whom no tumor can be identified. However, our data suggest that this procedure is contraindicated as these occult tumors are usually within the pancreatic head. Recent series suggest that previously missed gastrinomas are commonly in the duodenum. IOUS is not able to identify these tumors, but other methods can. Of 27 patients with 31 duodenal gastrinomas, palpation identified 19

  17. Endoscopic approach to the diagnosis of pancreatic cystic tumor

    PubMed Central

    Kawaguchi, Yoshiaki; Mine, Tetsuya

    2016-01-01

    Because of the aging of the population, prevalence of medical checkups, and advances in imaging studies, the number of pancreatic cystic lesions detected has increased. Once these lesions are detected, neoplastic cysts should be differentiated from non-neoplastic cysts. Furthermore, because of the malignant potential of some neoplastic pancreatic cysts, further differentiation between benign and malignant cysts should be made regardless of their size. Although endoscopic ultrasound (EUS) has a very high diagnostic performance for pancreatic cystic lesions among the various imaging modalities, EUS findings alone are insufficient for the differentiation of pancreatic cysts and diagnosis of malignancy. In addition, cytology by EUS-guided fine-needle aspiration (FNA) has a high specificity but a low sensitivity for diagnosing malignancy in pancreatic cystic tumors. The levels of amylase, lipase, and tumor markers in pancreatic cystic fluid are considered auxiliary parameters for diagnosis of benign and malignant cysts, and a definitive diagnosis of malignancy using these parameters is difficult. Thus, in addition to EUS, cytology by EUS-FNA, and cystic fluid analysis, new techniques based on EUS-guided through-the-needle imaging, such as confocal laser endomicroscopy and cystoscopy, have been explored in recent years. PMID:26909130

  18. Circulating Tumor Cells and Circulating Tumor DNA Provide New Insights into Pancreatic Cancer

    PubMed Central

    Gao, Yang; Zhu, Yayun; Yuan, Zhou

    2016-01-01

    Pancreatic cancer has a rather dismal prognosis mainly due to high malignance of tumor biology. Up to now, the relevant researches on pancreatic cancer lag behind seriously partly due to the obstacles for tissue biopsy, which handicaps the understanding of molecular and genetic features of pancreatic cancer. In the last two decades, liquid biopsy, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), is promising to provide new insights into the biological and clinical characteristics of malignant tumors. Both CTCs and ctDNA provide an opportunity for studying tumor heterogeneity, drug resistance, and metastatic mechanism for pancreatic cancer. Furthermore, they can also play important roles in detecting early-stage tumors, providing prognostic information, monitoring tumor progression and guiding treatment regimens. In this review, we will introduce the latest findings on biological features and clinical applications of both CTCs and ctDNA in pancreatic cancer. In a word, CTCs and ctDNA are promising to promote precision medicine in pancreatic cancer. PMID:27994495

  19. The Role of Tumor Cell-Derived Connective Tissue Growth Factor (CTGF/CCN2) in Pancreatic Tumor Growth

    PubMed Central

    Bennewith, Kevin L.; Huang, Xin; Ham, Christine M.; Graves, Edward E.; Erler, Janine T.; Kambham, Neeraja; Feazell, Jonathan; Yang, George P.; Koong, Albert

    2009-01-01

    Pancreatic cancer is highly aggressive and refractory to existing therapies. Connective tissue growth factor (CTGF/CCN2) is a fibrosis-related gene that is thought to play a role in pancreatic tumor progression. However, CCN2 can be expressed in a variety of cell types, and the contribution of CCN2 derived from either tumor cells or stromal cells as it affects the growth of pancreatic tumors is unknown. Using genetic inhibition of CCN2, we have discovered that CCN2 derived from tumor cells is a critical regulator of pancreatic tumor growth. Pancreatic tumor cells derived from CCN2 shRNA-expressing clones showed dramatically reduced growth in soft agar and when implanted subcutaneously. We also observed a role for CCN2 in the growth of pancreatic tumors implanted orthotopically, with tumor volume measurements obtained by PET imaging. Mechanistically, CCN2 protects cells from hypoxia-mediated apoptosis, providing an in vivo selection for tumor cells that express high levels of CCN2. We found that CCN2 expression and secretion was increased in hypoxic pancreatic tumor cells in vitro, and we observed co-localization of CCN2 and hypoxia in pancreatic tumor xenografts and clinical pancreatic adenocarcinomas. Furthermore, we found increased CCN2 staining in clinical pancreatic tumor tissue relative to stromal cells surrounding the tumor, supporting our assertion that tumor cell-derived CCN2 is important for pancreatic tumor growth. Taken together, these data improve our understanding of the mechanisms responsible for pancreatic tumor growth and progression, and also indicate that CCN2 produced by tumor cells represents a viable therapeutic target for the treatment of pancreatic cancer. PMID:19179545

  20. Cystic pancreatic neuroendocrine tumors: To date a diagnostic challenge.

    PubMed

    Caglià, Pietro; Cannizzaro, Maria Teresa; Tracia, Angelo; Amodeo, Luca; Tracia, Luciano; Buffone, Antonino; Amodeo, Corrado; Cannizzaro, Matteo Angelo

    2015-09-01

    Cystic PNETs are an uncommon neoplasms increasingly detected in current clinical practice which often present a diagnostic challenges to both the experienced radiologist and pathologist. The aim of this study was to review the available literature to summarize current data that compare and evaluate both the clinical and pathologic features of cystic pancreatic neuroendocrine tumors. A systematic review of the current literature was performed using the search engines EMBASE and PubMed to identify all studies reporting on cystic pancreatic neuroendocrine tumors. The MeSH search terms used were "cystic pancreatic neuroendocrine tumors", "endocrine neoplasms", and "pancreatic cysts". Multiple combinations of the keywords and MeSH terms were used. The clinical evaluation of cystic pancreatic lesions appears to suffer from same limitations despite the improvement in the diagnostic tools. Subsequently, we highlight diagnostic pitfalls and differential diagnosis of these cystic tumors. In this review we discuss current advances in the application of the imaging modalities and characteristics features with special emphasize on endoscopic ultrasound (EUS), and EUS guide fine needle aspiration (EUS-FNA). Cystic neuroendocrine tumor in the pancreas underlines the clinical impact of endoscopic ultrasound in the work-up of patients with unclear lesions in the pancreas. EUS-FNA cytology and cyst fluid analysis is a useful adjunct to abdominal imaging for the diagnosis of pancreatic cystic lesions. Due to the evident diagnostic difficulties, we hypothesize that cyst fluid characteristics, including cytomorphological features, is the most accurate test to achieve a preoperative diagnosis and to provide a basis for prognostic prediction. Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

  1. The Potential for Circulating Tumor Cells in Pancreatic Cancer Management

    PubMed Central

    Pimienta, Michael; Edderkaoui, Mouad; Wang, Ruoxiang; Pandol, Stephen

    2017-01-01

    Pancreatic cancer is one the most lethal malignancies. Only a small proportion of patients with this disease benefit from surgery. Chemotherapy provides only a transient benefit. Though much effort has gone into finding new ways for early diagnosis and treatment, average patient survival has only been improved in the order of months. Circulating tumor cells (CTCs) are shed from primary tumors, including pre-malignant phases. These cells possess information about the genomic characteristics of their tumor source in situ, and their detection and characterization holds potential in early cancer diagnosis, prognosis, and treatment. Liquid Biopsies present an alternative to tumor biopsy that are hard to sample. Below we summarize current methods of CTC detection, the current literature on CTCs in pancreatic cancer, and future perspectives. PMID:28626429

  2. Radical resection and enucleation in Chinese adolescents with pancreatic tumors

    PubMed Central

    Yao, Lie; Xie, Zhi-Bo; Jin, Chen; Jiang, Yong-Jian; Li, Ji; Yang, Feng; Lin, Quan-Jun; Fu, De-Liang

    2017-01-01

    Abstract Pancreatic tumors rarely occur in adolescents, and the appropriateness of radical resection for these patients remains controversial. Medical records were retrospectively reviewed for patients younger than 19 years who underwent radical resection or limited resection (enucleation) between 2000 and 2015. Patient demographics, clinical characteristics, operative details, growth, and survival were analyzed. During the study period, 11 adolescents (mean age, 16.18 years; standard deviation, 1.99; interquartile range, 15.0–18.0) underwent radical resection (n = 7) or enucleation (n = 4) to treat solid pseudopapillary tumors (n = 5), pancreatic neuroendocrine tumors (n = 5), or pancreatic ductal adenocarcinoma (n = 1). None of the 7 patients who underwent radical resection experienced recurrence or serious complications, while 3 of 4 patients who underwent enucleation experienced recurrence (P = 0.02). Recurrence-free survival was slightly longer in patients who underwent radical resection, and this procedure did not appear to affect adolescent growth and development. Radical resection might be safe and effective for adolescents with pancreatic tumors. PMID:28328854

  3. APC promoter is frequently methylated in pancreatic juice of patients with pancreatic carcinomas or periampullary tumors

    PubMed Central

    Ginesta, Mireia M.; Diaz-Riascos, Zamira Vanessa; Busquets, Juli; Pelaez, Núria; Serrano, Teresa; Peinado, Miquel Àngel; Jorba, Rosa; García-Borobia, Francisco Javier; Capella, Gabriel; Fabregat, Joan

    2016-01-01

    Early detection of pancreatic and periampullary neoplasms is critical to improve their clinical outcome. The present authors previously demonstrated that DNA hypermethylation of adenomatous polyposis coli (APC), histamine receptor H2 (HRH2), cadherin 13 (CDH13), secreted protein acidic and cysteine rich (SPARC) and engrailed-1 (EN-1) promoters is frequently detected in pancreatic tumor cells. The aim of the present study was to assess their prevalence in pancreatic juice of carcinomas of the pancreas and periampullary area. A total of 135 pancreatic juices obtained from 85 pancreatic cancer (PC), 26 ampullary carcinoma (AC), 10 intraductal papillary mucinous neoplasm (IPMN) and 14 chronic pancreatitis (CP) patients were analyzed. The methylation status of the APC, HRH2, CDH13, SPARC and EN-1 promoters was analyzed using methylation specific-melting curve analysis (MS-MCA). Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations were also tested with allele-specific quantitative polymerase chain reaction amplification. Out of the 5 promoters analyzed, APC (71%) and HRH2 (65%) were the most frequently methylated in PC juice. APC methylation was also detected at a high frequency in AC (76%) and IPMN (80%), but only occasionally observed in CP (7%). APC methylation had a high sensitivity (71–80%) for all types of cancer analyzed. The panel (where a sample scored as positive when ≥2 markers were methylated) did not outperform APC as a single marker. Finally, KRAS detection in pancreatic juice offered a lower sensitivity (50%) and specificity (71%) for detection of any cancer. APC hypermethylation in pancreatic juice, as assessed by MS-MCA, is a frequent event of potential clinical usefulness in the diagnosis of pancreatic and periampullary neoplasms. PMID:27602165

  4. EUS-Guided Antitumor Therapy for Pancreatic Tumors.

    PubMed

    Seo, Dong Wan

    2010-09-01

    Endoscopic ultrasound (EUS) is a very useful modality for the diagnosis and staging of pancreatic masses. With the advent of EUS-guided fine-needle aspiration technology, this modality has made a tremendous leap from imaging modality to histologic diagnosis and therapeutic intervention. EUS offers high-resolution images of and unparalleled access to the pancreas. After locating the tip of the echoendoscope in the duodenum or stomach, several drugs or local treatment modalities can be delivered directly into the pancreas. EUS-guided ethanol lavage with/without paclitaxel injection has been tested for the treatment of cystic tumors of the pancreas, with complete resolution of cystic tumor being observed in up to 70-80% of patients. Ethanol injection is also performed for the management of solid neuroendocrine tumors of the pancreas. Various type of EUS-guided injection have also been investigated for the treatment of pancreatic cancer. An activated allogenic mixed lymphocyte culture (Cytoimplant) was injected in patients with advanced pancreatic cancer. A replication-deficient adenovirus vector carrying the tumor necrosis factor-alpha gene was also delivered intratumorally by EUS. ONYX-015 is an oncolytic attenuated adenovirus that exhibits replication preferentially in malignant cells, causing cell death, and this has also been injected into pancreatic cancers under EUS guidance. EUS-guided local ablation therapies such as radiofrequency ablation, photodynamic therapy, and brachytherapy are also under investigation. EUS-guided fine-needle injection for various solid or cystic lesions is a rapidly expanding field. This article reviews the various applications of EUS for the treatment of pancreatic tumors.

  5. EUS-Guided Antitumor Therapy for Pancreatic Tumors

    PubMed Central

    2010-01-01

    Endoscopic ultrasound (EUS) is a very useful modality for the diagnosis and staging of pancreatic masses. With the advent of EUS-guided fine-needle aspiration technology, this modality has made a tremendous leap from imaging modality to histologic diagnosis and therapeutic intervention. EUS offers high-resolution images of and unparalleled access to the pancreas. After locating the tip of the echoendoscope in the duodenum or stomach, several drugs or local treatment modalities can be delivered directly into the pancreas. EUS-guided ethanol lavage with/without paclitaxel injection has been tested for the treatment of cystic tumors of the pancreas, with complete resolution of cystic tumor being observed in up to 70-80% of patients. Ethanol injection is also performed for the management of solid neuroendocrine tumors of the pancreas. Various type of EUS-guided injection have also been investigated for the treatment of pancreatic cancer. An activated allogenic mixed lymphocyte culture (Cytoimplant) was injected in patients with advanced pancreatic cancer. A replication-deficient adenovirus vector carrying the tumor necrosis factor-alpha gene was also delivered intratumorally by EUS. ONYX-015 is an oncolytic attenuated adenovirus that exhibits replication preferentially in malignant cells, causing cell death, and this has also been injected into pancreatic cancers under EUS guidance. EUS-guided local ablation therapies such as radiofrequency ablation, photodynamic therapy, and brachytherapy are also under investigation. EUS-guided fine-needle injection for various solid or cystic lesions is a rapidly expanding field. This article reviews the various applications of EUS for the treatment of pancreatic tumors. PMID:21103299

  6. Worst case optimization for interfractional motion mitigation in carbon ion therapy of pancreatic cancer.

    PubMed

    Steitz, Julian; Naumann, Patrick; Ulrich, Silke; Haefner, Matthias F; Sterzing, Florian; Oelfke, Uwe; Bangert, Mark

    2016-10-07

    The efficacy of radiation therapy treatments for pancreatic cancer is compromised by abdominal motion which limits the spatial accuracy for dose delivery - especially for particles. In this work we investigate the potential of worst case optimization for interfractional offline motion mitigation in carbon ion treatments of pancreatic cancer. We implement a worst case optimization algorithm that explicitly models the relative biological effectiveness of carbon ions during inverse planning. We perform a comparative treatment planning study for seven pancreatic cancer patients. Treatment plans that have been generated using worst case optimization are compared against (1) conventional intensity-modulated carbon ion therapy, (2) single field uniform dose carbon ion therapy, and (3) an ideal yet impractical scenario relying on daily re-planning. The dosimetric quality and robustness of the resulting treatment plans is evaluated using reconstructions of the daily delivered dose distributions on fractional control CTs. Idealized daily re-planning consistently gives the best dosimetric results with regard to both target coverage and organ at risk sparing. The absolute reduction of D 95 within the gross tumor volume during fractional dose reconstruction is most pronounced for conventional intensity-modulated carbon ion therapy. Single field uniform dose optimization exhibits no substantial reduction for six of seven patients and values for D 95 for worst case optimization fall in between. The treated volume (D>95 % prescription dose) outside of the gross tumor volume is reduced by a factor of two by worst case optimization compared to conventional optimization and single field uniform dose optimization. Single field uniform dose optimization comes at an increased radiation exposure of normal tissues, e.g. ≈2 Gy (RBE) in the mean dose in the kidneys compared to conventional and worst case optimization and ≈4 Gy (RBE) in D 1 in the spinal cord compared to worst case

  7. Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth.

    PubMed

    Muders, Michael H; Vohra, Pawan K; Dutta, Shamit K; Wang, Enfeng; Ikeda, Yasuhiro; Wang, Ling; Udugamasooriya, D Gomika; Memic, Adnan; Rupasinghe, Chamila N; Rupashinghe, Chamila N; Baretton, Gustavo B; Aust, Daniela E; Langer, Silke; Datta, Kaustubh; Simons, Michael; Spaller, Mark R; Mukhopadhyay, Debabrata

    2009-06-15

    Various studies have shown the importance of the GAIP interacting protein, COOH-terminus (GIPC, also known as Synectin) as a central adaptor molecule in different signaling pathways and as an important mediator of receptor stability. GIPC/Synectin is associated with different growth-promoting receptors such as insulin-like growth factor receptor I (IGF-IR) and integrins. These interactions were mediated through its PDZ domain. GIPC/Synectin has been shown to be overexpressed in pancreatic and breast cancer. The goal of this study was to show the importance of GIPC/Synectin in pancreatic cancer growth and to evaluate a possible therapeutic strategy by using a GIPC-PDZ domain inhibitor. Furthermore, the effect of targeting GIPC on the IGF-I receptor as one of its associated receptors was tested. The in vivo effects of GIPC/Synectin knockdown were studied after lentiviral transduction of luciferase-expressing pancreatic cancer cells with short hairpin RNA against GIPC/Synectin. Additionally, a GIPC-PDZ--targeting peptide was designed. This peptide was tested for its influence on pancreatic cancer growth in vitro and in vivo. Knockdown of GIPC/Synectin led to a significant inhibition of pancreatic adenocarcinoma growth in an orthotopic mouse model. Additionally, a cell-permeable GIPC-PDZ inhibitor was able to block tumor growth significantly without showing toxicity in a mouse model. Targeting GIPC was accompanied by a significant reduction in IGF-IR expression in pancreatic cancer cells. Our findings show that targeting GIPC/Synectin and its PDZ domain inhibits pancreatic carcinoma growth and is a potential strategy for therapeutic intervention of pancreatic cancer.

  8. Biochemical prognostic indicators for pancreatic neuroendocrine tumors and small bowel neuroendocrine tumors

    PubMed Central

    Cavaness, Keith; Celinski, Scott; Preskitt, John

    2014-01-01

    Pancreatic neuroendocrine tumors (PNETs) and small bowel neuroendocrine tumors (SBNETs) are rare tumors that are frequently diagnosed late in the course of the disease. Several biomarkers have been proposed in the literature as prognostic factors for patients with these tumors. This article discusses a recent publication in Annals of Surgical Oncology from the University of Iowa analyzing the effect of different biomarkers on survival in patients with PNETs and SBNETs. PMID:25493250

  9. [Classification of gastro-entero-pancreatic neuroendocrine tumors].

    PubMed

    Perren, A; Schmitt, A; Komminoth, P; Pavel, M

    2009-03-01

    Tumors of the disseminated/diffuse neuroendocrine system (NET) are characterized by a common phenotype. However, the biology varies according to histomorphology, endocrine symptoms and organ of origin. The WHO classification takes these differences into account and uses a common framework, where the parameters size and extent of invasion vary according to the organ of origin. In order to achieve a further standardization of reporting the European Neuroendocrine Tumor Society (ENETS) recently proposed a tumor-node-metastasis (TNM) staging and grading system for gastro-entero-pancreatic NET.

  10. Pancreastatin producing cell line from human pancreatic islet cell tumor.

    PubMed

    Funakoshi, A; Tateishi, K; Tsuru, M; Jimi, A; Wakasugi, H; Ikeda, Y; Kono, A

    1990-04-30

    It has been characterized that cell line QGP-1 derived from human non-functioning pancreatic islet cell tumor produces human pancreastatin. Exponentially growing cultures produced 5.7 fmol of pancreastatin/10(6) cells/hr. Human pancreastatin immunoreactivities in plasma and tumor after xenografting with QGP-1 into nude mouse were 92.7 fmol/ml and 160.2 pmol/g wet weight, respectively. Immunocytochemical study revealed both chromogranin A and pancreastatin immunoreactive cells in the tumor. Gel filtrations of culture medium and tumor extract identified heterogenous molecular forms of PST-LI which eluted as large and smaller molecular species. These results suggest that plasma pancreastatin levels may be useful as a tumor marker of endocrine tumor of the pancreas, and the pancreastatin producing cell line may be useful for studies of the mechanism of secretions and processing of chromogranin A and pancreastatin.

  11. Targeting GIPC/Synectin in Pancreatic Cancer Inhibits Tumor Growth

    PubMed Central

    Muders, Michael H.; Vohra, Pawan K.; Dutta, Shamit K; Wang, Enfeng; Ikeda, Yasuhiro; Wang, Ling; Udugamasooriya, D. Gomika; Memic, Adnan; Rupashinghe, Chamila N.; Baretton, Gustavo B.; Aust, Daniela E.; Langer, Silke; Datta, Kaustubh; Simons, Michael; Spaller, Mark R.; Mukhopadhyay, Debabrata

    2009-01-01

    Translational Relevance The five year survival rate in patients with ductal adenocarcinoma of the pancreas is less than 4%. Accordingly, new targets for the treatment of this deadly disease are urgently needed. In this study, we show that targeting GAIP interacting protein C-terminal (GIPC, also known as Synectin) and its PDZ-domain reduces pancreatic cancer growth significantly in vitro and in vivo. Additionally, the blockage of GIPC/Synectin was accompanied by a reduction of IGF-1R protein levels. In summary, the use of a GIPC-PDZ domain inhibitor may be a viable option in the treatment of pancreatic adenocarcinoma in future. Purpose Various studies have demonstrated the importance of GAIP interacting protein, C-terminus (GIPC, also known as Synectin) as a central adaptor molecule in different signaling pathways and as an important mediator of receptor stability. GIPC/Synectin is associated with different growth promoting receptors like IGF-1R and integrins. These interactions were mediated through its PDZ domain. GIPC/Synectin has been shown to be overexpressed in pancreatic and breast cancer. The goal of this study was to demonstrate the importance of GIPC/Synectin in pancreatic cancer growth and to evaluate a possible therapeutic strategy by using a GIPC-PDZ domain inhibitor. Furthermore, the effect of targeting GIPC on the IGF-1 receptor as one of its associated receptors was tested. Experimental Design In vivo effects of GIPC/Synectin knockdown were studied after lentiviral transduction of luciferase-expressing pancreatic cancer cells with shRNA against GIPC/Synectin. Additionally, a GIPC-PDZ-targeting peptide was designed. This peptide was tested for its influence on pancreatic cancer growth in vitro and in vivo. Results Knockdown of GIPC/Synectin led to a significant inhibition of pancreatic adenocarcinoma growth in an orthotopic mouse model. Additionally, a cell-permeable GIPC-PDZ inhibitor was able to block tumor growth significantly without showing

  12. Metastatic Insulinoma Following Resection of Nonsecreting Pancreatic Islet Cell Tumor

    PubMed Central

    Gordon, Ilyssa O.; Van Ha, Thuong G.; Kaplan, Edwin L.; Philipson, Louis H.

    2013-01-01

    A 56-year-old woman presented to our clinic for recurrent hypoglycemia after undergoing resection of an incidentally discovered nonfunctional pancreatic endocrine tumor 6 years ago. She underwent a distal pancreatectomy and splenectomy, after which she developed diabetes and was placed on an insulin pump. Pathology showed a pancreatic endocrine neoplasm with negative islet hormone immunostains. Two years later, computed tomography scan of the abdomen showed multiple liver lesions. Biopsy of a liver lesion showed a well-differentiated neuroendocrine neoplasm, consistent with pancreatic origin. Six years later, she presented to clinic with 1.5 years of recurrent hypoglycemia. Laboratory results showed elevated proinsulin, insulin levels, and c-peptide levels during a hypoglycemic episode. Computed tomography scan of the abdomen redemonstrated multiple liver lesions. Repeated transarterial catheter chemoembolization and microwave thermal ablation controlled hypoglycemia. The unusual features of interest of this case include the transformation of nonfunctioning pancreatic endocrine tumor to a metastatic insulinoma and the occurrence of atrial flutter after octreotide for treatment. PMID:26425568

  13. [Pancreatic tumors--pessimism, optimism or realism?].

    PubMed

    Leffler, J; Dvorák, J

    1998-08-01

    Among 35 patients with the preoperative diagnosis of a tumour of the head of the pancreas who had a radical operation at the Surgical Clinic of the Second Medical Faculty Charles University in Prague-Motol between January 1995 and March 1998 a malignant tumour was confirmed in 24 instances. Another nine patients had a histological finding of chronic pancreatitis and the remaining two patients a benign cystadenoma of the pancreas. The 30-day mortality in the whole group is 5.7% (2/35). Both deaths within 30 days after surgery were due to massive haemorrhage into the upper GIT in patients with pancreatic cancer. The haemorrhage developed within 21 and 30 days after surgery. The source of haemorrhage was not proved unequivocally, neither clinically nor post mortem. Obviously late haemorrhage from some gastrointestinal anastomosis was involved. From a total of 24 patients after Whipple's operation on account of a malignant tumour of the head of the pancreas nine died. The mean survival period was seven months after surgery. Fifteen patients survive and after a mean follow-up period of 14 months the median of survival calculated to the date of March 31 1998 is 17 months for stage UICC I and five months for stage UICC III. Because of the short follow-up period the results cannot be compared properly with data in the contemporary literature but they are promising for further work in this sphere of surgery and evidence that it is correct to refute the nihilist view held in the past. Hitherto achieved therapeutic results in this country and abroad certainly do not justify yet an optimistic view as regards the perspective of patients with carcinoma of the pancreas.

  14. Unexpected pheochromocytoma presenting as a pancreatic tumor: A case report

    PubMed Central

    HUANG, YI-HSUAN; LIAW, WEN-JINN; KUO, CHANG-PO; WU, ZHI-FU; CHERNG, CHEN-HWAN; YU, JYH-CHERNG; HORNG, HUEI-CHI; HUANG, SHUN-TSUNG

    2013-01-01

    A 54-year-old female presented with a large pancreatic tumor of the tail during a regular physical examination. The patient underwent surgical intervention and the surgeon identified that the tumor originated from the retroperitoneal region. Markedly severe hemodynamic fluctuations occurred during the manipulation of the tumor and continued to occur subsequent to the tumor being removed. The vital signs were adequately managed and the surgery was successful without complications. The patient was discharged without any sequelae days later. The pathology report indicated a diagnosis of pheochromocytoma. Unexpected pheochromocytoma may lead to a fatal hypertensive crisis with catastrophic sequelae during surgery. The peri-operative management of pheochromocytoma remains a complicated challenge that requires intensive pre-operative preparation and vigilant peri-operative care. For surgeons and anesthesiologists who may encounter an unexpected hypertensive crisis during abdominal tumor surgery, undiagnosed pheochromocytoma should always be considered. PMID:24137420

  15. Robotic left pancreatectomy for pancreatic solid pseudopapillary tumor.

    PubMed

    Ntourakis, Dimitrios; Marzano, Ettore; De Blasi, Vito; Oussoultzoglou, Elie; Jaeck, Daniel; Pessaux, Patrick

    2011-03-01

    Solid pseudopapillary pancreatic tumors of pancreas are a rare entity, seen most often in females in their second or third decades. Although previously believed to be benign, this tumor is currently considered a low-grade malignant epithelial neoplasm with low metastatic rate and high overall survival.1,2 Its resection could be performed by robotic technique with respect to oncological principles to avoid tumor cell dissemination.3 In this multimedia article, we present a 28-year-old female with a history of hyperthyroidism who underwent a computed tomography (CT) scan because of a persistent high C-reactive protein level following caesarean section. This CT scan revealed a 7-cm cystic lesion of the pancreatic tail. The serum tumor marker CA 19-9 was normal. Further investigation with an magnetic resonance imaging (MRI) scan showed that the lesion was macrocystic with internal septas compatible with a solid pseudopapillary neoplasm.4 The patient was treated with robotic distal splenopanceatectomy (video). The operative time was 5 h with an estimated blood loss of 250 mL. No blood transfusion was necessary. The postoperative period was uneventful, and she was discharged on postoperative day 8. The histological finding revealed a solid pseudopapillary tumor of the pancreas pT2pN0 (0/14 lymph nodes removed). There was no evidence of clinical, biological, and radiological pancreatic fistula, and a control CT scan on postoperative day 8 did not show any abdominal fluid collection. The patient's 1 month follow-up was normal. The robotic distal splenopancreatectomy is a procedure that offers some technical and oncological advantages over the already described minimally invasive techniques for distal pancreatic tumors.5,6 These advantages are mainly due to the stability of the operative field, to the 3D and magnified vision, and to the articulated robotic arms.7-9 The 3D representation and the stability of the operative field facilitate the performance of operative

  16. Morbidity and mortality of pancreatic tumors undergoing surgical treatment

    PubMed Central

    ZENI, Luiza Bueno; RUSSI, Ricardo Fantazzini; FIALHO, Alexandre Faleiro; FONSECA, Ana Luiza Pagani; SOMBRIO, Lyara Schaefer; ROCHA, Igor Cunha

    2014-01-01

    Background Pancreatic cancer has a high mortality rate due to late diagnosis and aggressive behavior. The prognosis is poor, with 5-year survival occurring in less than 5% of cases. Aim To analyze demographic characteristics, comorbidities, type of procedure and early postoperative complications of patients with pancreatic cancer submitted to surgical treatment. Methods Cross-sectional study with analysis of 28 medical records of patients with malignant tumors of the pancreas in a 62 month. Data collection was performed from the medical records of the hospital. Results Of the total, 53,6% were male and the mean age was 60.25 years. According to the procedure, 53,6% was submitted to duodenopancreactectomy the remainder to biliodigestive derivation or distal pancreatectomy. The ductal adenocarcinoma occurred in 82,1% and 92,9% of tumors were located in the pancreatic head. Early postoperative complications occurred in 64,3% of cases and the most prevalent was intra-abdominal abscess (32,1%). Among duodenopancreactectomies 77,8% had early postoperative complications. Conclusion Its necessary to encourage early detection of tumors of the pancreas to raise the number operations with curative intent. Refinements in surgical techniques and surgical teams can diminish postoperative complications and, so, operative morbimortality can also decrease over time. PMID:25626938

  17. A Systematic Review of Proinsulin-Secreting Pancreatic Neuroendocrine Tumors.

    PubMed

    Murtha, Timothy D; Lupsa, Beatrice C; Majumdar, Sachin; Jain, Dhanpat; Salem, Ronald R

    2017-08-01

    Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous group of islet cell-derived neoplasms with a propensity toward hormone production. Among PNETs, proinsulin-secreting tumors (proinsulinomas) are exceedingly rare. The objective of this study is to collect and summarize the existing literature to provide a comprehensive evaluation of this uncommon disease. A systematic review was performed to characterize the clinicopathologic features of proinsulinoma. Using the electronic biomedical databases PubMed, Ovid Medline, and Embase, 316 publications were screened for relevance of which 14 were selected. We also present two patients with proinsulinoma treated at Yale New Haven Hospital. Of the 16 patients included in the study, the mean age was 56.8 and there was a 2:1 female predominance. The majority of patients presented with symptomatic hypoglycemia with normal or low insulin levels. Median tumor diameter was 1.2 cm and 80% were located in the body and tail of the pancreas. Following resection, most patients had normalization of hormonal levels without recurrence (75%; 12/16). Proinsulinomas are rare pancreatic neuroendocrine tumors that have the potential to cause hypoglycemia. While insulinomas and proinsulin-secreting tumors have many physiologic parallels, these cases illustrate several key distinctions in their diagnosis and management.

  18. Identification of peptides that bind to irradiated pancreatic tumor cells

    SciTech Connect

    Huang Canhui; Liu, Xiang Y.; Rehemtulla, Alnawaz; Lawrence, Theodore S. . E-mail: tsl@med.umich.edu

    2005-08-01

    Purpose: Peptides targeting tumor vascular cells or tumor cells themselves have the potential to be used as vectors for delivering either DNA in gene therapy or antitumor agents in chemotherapy. We wished to determine if peptides identified by phage display could be used to target irradiated pancreatic cancer cells. Methods and Materials: Irradiated Capan-2 cells were incubated with 5 x 10{sup 12} plaque-forming units of a phage display library. Internalized phage were recovered and absorbed against unirradiated cells. After five such cycles of enrichment, the recovered phage were subjected to DNA sequencing analysis and synthetic peptides made. The binding of both phage and synthetic peptides was evaluated by fluorescence staining and flow cytometry in vitro and in vivo. Results: We identified one 12-mer peptide (PA1) that binds to irradiated Capan-2 pancreatic adenocarcinoma cells but not to unirradiated cells. The binding of peptide was significant after 48 h incubation with cells. In vivo experiments with Capan-2 xenografts in nude mice demonstrated that these small peptides are able to penetrate tumor tissue after intravenous injections and bind specifically to irradiated tumor cells. Conclusion: These data suggest that peptides can be identified that target tumors with radiation-induced cell markers and may be clinically useful.

  19. Image-guided tumor motion modeling and tracking

    NASA Astrophysics Data System (ADS)

    Zhang, J.; Wu, Y.; Liu, W.; Christensen, J.; Tai, A.; Li, A. X.

    2009-02-01

    Radiation therapy (RT) is an important procedure in the treatment of cancer in the thorax and abdomen. However, its efficacy can be severely limited by breathing induced tumor motion. Tumor motion causes uncertainty in the tumor's location and consequently limits the radiation dosage (for fear of damaging normal tissue). This paper describes a novel signal model for tumor motion tracking/prediction that can potentially improve RT results. Using CT and breathing sensor data, it provides a more accurate characterization of the breathing and tumor motion than previous work and is non-invasive. The efficacy of our model is demonstrated on patient data.

  20. Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice.

    PubMed

    Endo, Sho; Nakata, Kohei; Ohuchida, Kenoki; Takesue, Shin; Nakayama, Hiromichi; Abe, Toshiya; Koikawa, Kazuhiro; Okumura, Takashi; Sada, Masafumi; Horioka, Kohei; Zheng, Biao; Mizuuchi, Yusuke; Iwamoto, Chika; Murata, Masaharu; Moriyama, Taiki; Miyasaka, Yoshihiro; Ohtsuka, Takao; Mizumoto, Kazuhiro; Oda, Yoshinao; Hashizume, Makoto; Nakamura, Masafumi

    2017-05-01

    Pancreatic stellate cells (PSCs) change from a quiescent to activated state in the tumor environment and secrete extracellular matrix (ECM) molecules and cytokines to increase the aggressiveness of tumors. However, it is not clear how PSCs are activated to produce these factors, or whether this process can be inhibited. PSCs have morphologic and functional similarities to hepatic stellate cells, which undergo autophagy to promote fibrosis and tumor growth. We investigated whether autophagy activates PSCs, which promotes development of the tumor stroma and growth of pancreatic tumors in mice. We used immunofluorescence microscopy and immunohistochemistry to analyze pancreatic tumor specimens from 133 patients who underwent pancreatectomy in Japan from 2000 to 2009. PSCs were cultured from pancreatic tumor tissues or tissues of patients with chronic pancreatitis; these were analyzed by immunofluorescence microscopy, immunoblots, quantitative reverse transcription polymerase chain reaction, and in assays for invasiveness, proliferation, and lipid droplets. Autophagy was inhibited in PSCs by administration of chloroquine or transfection with small interfering RNAs. Proteins were knocked down in immortalized PSCs by expression of small hairpin RNAs. Cells were transplanted into pancreatic tails of nude mice, and tumor growth and metastasis were quantified. Based on immunohistochemical analyses, autophagy was significantly associated with tumor T category (P = .018), histologic grade (P = .001), lymph node metastases (P < .001), stage (P = .009), perilymphatic invasion (P = .001), and perivascular invasion (P = .003). Autophagy of PSCs was associated with shorter survival times of patients with pancreatic cancer. PSC expression of microtubule-associated protein 1 light chain 3, a marker of autophagosomes, was associated with poor outcomes (shorter survival time, disease recurrence) for patients with pancreatic cancer (relative risk of shorter survival time, 1

  1. Tumor Reduction in Primary and Metastatic Pancreatic Cancer Lesions With nab-Paclitaxel and Gemcitabine

    PubMed Central

    Kunzmann, Volker; Ramanathan, Ramesh K.; Goldstein, David; Liu, Helen; Ferrara, Stefano; Lu, Brian; Renschler, Markus F.; Von Hoff, Daniel D.

    2017-01-01

    Objectives Results from the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) led to approval of nab-paclitaxel plus gemcitabine for first-line treatment of metastatic pancreatic cancer. The current analysis evaluated the effects of nab-paclitaxel plus gemcitabine versus gemcitabine on primary pancreatic and metastatic lesions. Methods In this analysis of the previously described MPACT trial, changes in pancreatic and metastatic tumor burden were assessed using independently measured diameters of lesions on computed tomography or magnetic resonance imaging scans. Changes in the sums of longest tumor diameters were summarized using descriptive statistics and were included in a multivariate analysis of overall survival. Results Primary pancreatic lesion measurement was feasible. Reductions in primary pancreatic tumor burden and metastatic burden from baseline to nadir were significantly greater with nab-paclitaxel plus gemcitabine versus gemcitabine. Baseline pancreatic tumor burden was independently predictive of survival. Both regimens elicited linear reductions in primary pancreatic and metastatic tumor burden through time. There was a high within-patient concordance of tumor changes between primary pancreatic lesions and metastatic lesions. Conclusions This analysis of MPACT demonstrated significant tumor shrinkage benefit for nab-paclitaxel plus gemcitabine in both primary pancreatic and metastatic lesions, supporting ongoing evaluation of this regimen in locally advanced disease. PMID:27841795

  2. 24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development

    PubMed Central

    Soncini, Matias; Corna, Gianfranca; Moresco, Marta; Coltella, Nadia; Restuccia, Umberto; Maggioni, Daniela; Raccosta, Laura; Lin, Chin-Yo; Invernizzi, Francesca; Crocchiolo, Roberto; Doglioni, Claudio; Traversari, Catia; Bachi, Angela; Bernardi, Rosa; Bordignon, Claudio; Gustafsson, Jan-Åke; Russo, Vincenzo

    2016-01-01

    Cells in the tumor microenvironment may be reprogrammed by tumor-derived metabolites. Cholesterol-oxidized products, namely oxysterols, have been shown to favor tumor growth directly by promoting tumor cell growth and indirectly by dampening antitumor immune responses. However, the cellular and molecular mechanisms governing oxysterol generation within tumor microenvironments remain elusive. We recently showed that tumor-derived oxysterols recruit neutrophils endowed with protumoral activities, such as neoangiogenesis. Here, we show that hypoxia inducible factor-1a (HIF-1α) controls the overexpression of the enzyme Cyp46a1, which generates the oxysterol 24-hydroxycholesterol (24S-HC) in a pancreatic neuroendocrine tumor (pNET) model commonly used to study neoangiogenesis. The activation of the HIF-1α–24S-HC axis ultimately leads to the induction of the angiogenic switch through the positioning of proangiogenic neutrophils in proximity to Cyp46a1+ islets. Pharmacologic blockade or genetic inactivation of oxysterols controls pNET tumorigenesis by dampening the 24S-HC–neutrophil axis. Finally, we show that in some human pNET samples Cyp46a1 transcripts are overexpressed, which correlate with the HIF-1α target VEGF and with tumor diameter. This study reveals a layer in the angiogenic switch of pNETs and identifies a therapeutic target for pNET patients. PMID:27671648

  3. Variation of tumoral marker after radiofrequency ablation of pancreatic adenocarcinoma

    PubMed Central

    Barbi, Emilio; Girelli, Roberto; Tinazzi Martini, Paolo; De Robertis, Riccardo; Ciaravino, Valentina; Salvia, Roberto; Butturini, Giovanni; Frigerio, Isabella; Milazzo, Teresa; Crosara, Stefano; Paiella, Salvatore; Pederzoli, Paolo; Bassi, Claudio

    2016-01-01

    Background To evaluate the correlation between variations of CA 19.9 blood levels and the entity of necrosis at CT after radiofrequency ablation (RFA) of unresectable pancreatic adenocarcinoma. Methods In this study, from June 2010 to February 2014, patients with diagnosis of unresectable and not metastatic pancreatic ductal adenocarcinoma, expressing tumor marker CA 19.9, treated with RFA procedure were included. All these patients underwent RFA. CT study was performed 1 week after RFA. The dosage of CA 19.9 levels was performed 1 month after RFA. Features of necrosis at CT, as mean entity, density and necrosis percentages compared to the original lesion, were evaluated and compared by using t-test with CA 19.9 blood levels variations after RFA procedure. Results In this study were included 51 patients with diagnosis of unresectable and not metastatic pancreatic ductal adenocarcinoma, expressing tumor marker CA 19.9, treated with RFA procedure and with CT study and CA 19.9 available for analysis. After the procedure, CA 19.9 blood levels reduced in 24/51 (47%), remained stable in 10/51 (20%) and increased in 17/51 (33%). In patients with CA 19.9 levels reduced, the tumor marker were reduced less than 20% in 4/24 (17%) and more than 20% in 20/24 (83%); instead the tumor marker were reduced less than 30% in 8/24 (33%) and more than 30% in 16/24 (67%). At CT scan necrotic area density difference was not statistically significant. Also there was no statistically significant difference among the mean area, the mean volume and the mean ablation volume in percentage related to the treated tumor among the three different groups of patients divided depending on the CA 19.9 blood levels. But a tendency to a statistically significant difference was found in comparing the mean percentage of ablation volume between two subgroups of patients with a decrease of CA 19.9 levels with less or more than 20% reduction of tumor markers and between two subgroups with less or more than

  4. Pancreatic Candidiasis That Mimics a Malignant Pancreatic Cystic Tumor on Magnetic Resonance Imaging: A Case Report in an Immunocompetent Patient.

    PubMed

    Seong, Minjung; Kang, Tae Wook; Ha, Sang Yun

    2015-01-01

    Candida is a commensal organism that is frequently found in the human gastrointestinal tract. It is the most common organism that causes pancreatic fungal infections. However, magnetic resonance imaging findings of Candida infection in the pancreas have not been described. We report imaging findings of pancreatic candidiasis in a patient in immunocompetent condition. It presented as a multi-septated cystic mass with a peripheral solid component in the background of pancreatitis and restricted diffusion on diffusion-weighted image that mimicked a malignant pancreatic cystic tumor.

  5. Multi-detector row CT of pancreatic islet cell tumors.

    PubMed

    Horton, Karen M; Hruban, Ralph H; Yeo, Charles; Fishman, Elliot K

    2006-01-01

    Pancreatic islet cell tumors (ICTs) are neuroendocrine neoplasms that produce and secrete hormones to a variable degree. These neoplasms can present a diagnostic challenge, both clinically and radiologically. ICTs can be classified as either syndromic or nonsyndromic on the basis of their clinical manifestations. Multi-detector row computed tomography (CT) plays an important role in the diagnosis and staging of both syndromic and nonsyndromic ICTs. In general, syndromic ICTs are less than 3 cm in size. They are typically hyperenhancing and are usually best seen on CT scans obtained during the arterial phase. Nonsyndromic ICTs tend to be larger than syndromic ICTs at presentation and are more likely to be cystic or necrotic. It is important for the radiologist to be familiar with appropriate CT protocol for the evaluation of patients with suspected pancreatic ICT and to understand the variable CT appearances of these neoplasms. (c) RSNA, 2006.

  6. [Tumor markers in the diagnosis of pancreatic cancer].

    PubMed

    Cappelli, G; Paladini, S; D'Agata, A

    1999-01-01

    The difficulty in an early diagnosis of pancreatic cancer is in the absence of early symptoms due to lower limit of detection of the actual imaging techniques. Clinical symptoms like weight loss, abdominal pain and jaundice indicate an advanced cancer stage. Today 50% of pancreatic tumors are diagnosed in advanced metastatic stage and only 20-30% show resectable cancer. Ultrasound and determination of a mucine like antigen as CA 19-9, CA 50 and CA 195 seem to allow an earlier diagnosis with a higher rate of resective surgery and a prolonged survival for these patients. The mucines are high molecular weight glycoproteins consistent of a backbone protein to which oligosaccarides are attached. The linkage of carbohydrate to the peptide is termed O-glycosidic and involves the hydroxylic groups of serine or threonine with N-acetylglucosamine. Only the backbone proteins are genetically determined (genes MUC). The gangliosides are the same or derivative of Lewis antigen. CA 19-9, CA 50 and CA 195 are assays directed to different epitopes probably present on the same mucinous antigen. These epitopes are not present in different mucines as CA 15-3, CA 125 and TAG 72. Recently other two mucines are emploied CA 242 and CAM 17.1 but they are not better than CA 19-9. The use of a "triplet" of tumor markers as CA 19-9, CA 125 and CEA is the best diagnostic tool for cancer of pancreas in an "integrated" use with ultrasonographic evaluation of the lesion. CA 19-9 permits differential diagnosis from neuroendocrine tumor or pancreatitis, the values of CA 125 and CEA are useful in the evaluation of the stage, resectability and prognosis of pancreatic cancer. The recent use of CA19-9 for the evaluation of radiochemotherapy in preoperative management of the patient is a mode of a well known application of tumor markers in a kinetic evaluation of the tumor for the radicality of therapy, follow-up, recurrence and the effectiveness of the palliative therapy.

  7. Pancreatic tumor cell secreted CCN1/Cyr61 promotes endothelial cell migration and aberrant neovascularization.

    PubMed

    Maity, Gargi; Mehta, Smita; Haque, Inamul; Dhar, Kakali; Sarkar, Sandipto; Banerjee, Sushanta K; Banerjee, Snigdha

    2014-05-16

    The complex signaling networks between cancer cells and adjacent endothelial cells make it challenging to unravel how cancer cells send extracellular messages to promote aberrant vascularization or tumor angiogenesis. Here, in vitro and in vivo models show that pancreatic cancer cell generated unique microenvironments can underlie endothelial cell migration and tumor angiogenesis. Mechanistically, we find that pancreatic cancer cell secreted CCN1/Cyr61 matricellular protein rewires the microenvironment to promote endothelial cell migration and tumor angiogenesis. This event can be overcome by Sonic Hedgehog (SHh) antibody treatment. Collectively, these studies identify a novel CCN1 signaling program in pancreatic cancer cells which activates SHh through autocrine-paracrine circuits to promote endothelial cell migration and tumor angiogenesis and suggests that CCN1 signaling of pancreatic cancer cells is vital for the regulation of tumor angiogenesis. Thus CCN1 signaling could be an ideal target for tumor vascular disruption in pancreatic cancer.

  8. Prostate-Specific Membrane Antigen (PSMA) Avid Pancreatic Neuroendocrine Tumor.

    PubMed

    Vamadevan, Shankar; Shetty, Deepa; Le, Ken; Bui, Chuong; Mansberg, Robert; Loh, Han

    2016-10-01

    Ga-PSMA PET/CT is increasingly used to evaluate recurrent prostatic malignancy due to its high specificity. A 75-year-old man with a previous history of treated prostate cancer 3 years earlier presented with rising prostate-specific antigen (PSA) level and underwent Ga-PSMA PET/CT which demonstrated a PSMA-avid focus in the neck of the pancreas. Triple-phase abdominal CT demonstrated enhancement in the arterial phase and to a lesser extent the venous phase of a soft tissue mass in the neck of the pancreas. Cytological and histopathological examination of the soft tissue mass confirmed a low-grade pancreatic neuroendocrine tumor.

  9. A renaissance in therapeutic options for pancreatic neuroendocrine tumors.

    PubMed

    Kunz, Pamela L

    2012-01-01

    The field of pancreatic neuroendocrine tumors (NETs) has seen a remarkable renaissance in recent years with exponential increases in published research, clinical trials, and U.S. Food and Drug Administration (FDA)-approved treatments. Surgical resection remains the foundation for management of locoregional disease. However, for patients with advanced disease, novel therapeutic options have emerged. Two separate randomized placebo-controlled studies have shown prolonged progression-free survival (PFS) with everolimus or sunitinib. Future studies are designed to answer questions about the role of somatostatin analogs as antiproliferative agents, combinations of biologic therapies, and new cytotoxic chemotherapy backbones.

  10. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances

    PubMed Central

    Ito, Tetsuhide; Igarashi, Hisato; Jensen, Robert T.

    2013-01-01

    Pancreatic neuroendocrine tumors (pNETs) comprise with gastrointestinal carcinoids, the main groups of gastrointestinal neuroendocrine tumors (GI-NETs). Although these two groups of GI-NETs share many features including histological aspects; over-/ectopic expression of somatostatin receptors; the ability to ectopically secrete hormones/peptides/amines which can result in distinct functional syndromes; similar approaches used for tumor localization and some aspects of treatment, it is now generally agreed they should be considered separate. They differ in their pathogenesis, hormonal syndromes produced, many aspects of biological behavior and most important, in their response to certain anti-tumor treatment (chemotherapy, molecular targeted therapies). In this chapter the clinical features of the different types of pNETs will be considered as well as aspects of their diagnosis and medical treatment of the hormone-excess state. Emphasis will be on controversial areas or recent advances. The other aspects of the management of these tumors (surgery, treatment of advanced disease, tumor localization) are not dealt with here, because they are covered in other chapters in this volume. PMID:23582916

  11. Chemotherapy and metformin in pancreatic adenocarcinoma and neuroendocrine tumors.

    PubMed

    Burney, Saira; Khawaja, Khadija Irfan; Saif, Muhammad Wasif; Masud, Faisal

    2014-07-28

    Pancreatic cancer, despite being a relatively less commonly occurring cancer is among the deadliest ones, leading to a grave prognosis. Surgery stands as the mainstay of treatment of pancreatic cancer but is an option in less than 15% patients owing to the late presentation of the tumor. Chemotherapy offers an important part of treatment but can adversely affect the quality of life because of devastating side effects and has limited survival benefit. Unavailability of effective and less toxic treatment options for pancreatic cancer has prompted the search for new treatment strategies. One such drug being considered for its potential anti-neoplastic role is the time-tested and widely used oral hypoglycemic drug, metformin. Metformin is proposed to target metabolic pathways involved in tumorigenesis, specifically the AMPK-mTOR complex. Epidemiological evidence is mounting in favor of its role in various cancers both for treatment and prophylaxis. Herein, we aim to summarize the epidemiological data on metformin as a potential anti-cancer drug in various cancers followed by a look at some of the abstracts relating to this topic that were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2014.

  12. Extrathyroidal Calcitonin Secreting Tumors: Pancreatic Neuroendocrine Tumors in Patients With Multinodular Goiter: Two Case Reports.

    PubMed

    Giannetta, Elisa; Gianfrilli, Daniele; Pozza, Carlotta; Lauretta, Rosa; Graziadio, Chiara; Sbardella, Emilia; Baroli, Alberto; Caronna, Roberto; Chirletti, Piero; Lenzi, Andrea; Isidori, Andrea M

    2016-01-01

    Calcitonin is the hallmark of medullary thyroid carcinoma. However, extrathyroidal neuroendocrine tumors can also release calcitonin.We report 2 cases of calcitonin-secreting pancreatic tumors found in asymptomatic patients with thyroid nodules referred to our center within 11 months.Case 1: A man initially referred for thyroid nodule characterization was found to have hypercalcitoninemia (>200 pg/mL) during non-neoplastic fine-needle aspiration.Case 2: A woman evaluated for liver metastasis was found to have hypercalcitoninemia and multinodular goiter.Our research emphasizes that marked hypercalcitoninemia in the presence of thyroid nodules is not necessarily due to medullary thyroid carcinoma; awareness of this could avoid unnecessary thyroidectomy. The lack of specific symptoms related to hypercalcitoninemia may be the reason that the prevalence of calcitonin-secreting pancreatic tumors is underestimated.

  13. Extrathyroidal Calcitonin Secreting Tumors: Pancreatic Neuroendocrine Tumors in Patients With Multinodular Goiter

    PubMed Central

    Giannetta, Elisa; Gianfrilli, Daniele; Pozza, Carlotta; Lauretta, Rosa; Graziadio, Chiara; Sbardella, Emilia; Baroli, Alberto; Caronna, Roberto; Chirletti, Piero; Lenzi, Andrea; Isidori, Andrea M.

    2016-01-01

    Abstract Calcitonin is the hallmark of medullary thyroid carcinoma. However, extrathyroidal neuroendocrine tumors can also release calcitonin. We report 2 cases of calcitonin-secreting pancreatic tumors found in asymptomatic patients with thyroid nodules referred to our center within 11 months. Case 1: A man initially referred for thyroid nodule characterization was found to have hypercalcitoninemia (>200 pg/mL) during non-neoplastic fine-needle aspiration. Case 2: A woman evaluated for liver metastasis was found to have hypercalcitoninemia and multinodular goiter. Our research emphasizes that marked hypercalcitoninemia in the presence of thyroid nodules is not necessarily due to medullary thyroid carcinoma; awareness of this could avoid unnecessary thyroidectomy. The lack of specific symptoms related to hypercalcitoninemia may be the reason that the prevalence of calcitonin-secreting pancreatic tumors is underestimated. PMID:26817871

  14. Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1.

    PubMed

    Machado, Marcel Cerqueira Cesar

    2012-01-01

    Surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. Presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. Of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. Non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. The vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. The usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. Surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. Some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. Furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. Hepatic trans-arterial chemo-embolization is usually associated with surgical resection. Liver transplantation may be needed for select cases. Finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and localization of

  15. Islet Cells Serve as Cells of Origin of Pancreatic Gastrin-Positive Endocrine Tumors.

    PubMed

    Bonnavion, Rémy; Teinturier, Romain; Jaafar, Rami; Ripoche, Doriane; Leteurtre, Emmanuelle; Chen, Yuan-Jia; Rehfeld, Jens F; Lepinasse, Florian; Hervieu, Valérie; Pattou, François; Vantyghem, Marie-Christine; Scoazec, Jean-Yves; Bertolino, Philippe; Zhang, Chang Xian

    2015-10-01

    The cells of origin of pancreatic gastrinomas remain an enigma, since no gastrin-expressing cells are found in the normal adult pancreas. It was proposed that the cellular origin of pancreatic gastrinomas may come from either the pancreatic cells themselves or gastrin-expressing cells which have migrated from the duodenum. In the current study, we further characterized previously described transient pancreatic gastrin-expressing cells using cell lineage tracing in a pan-pancreatic progenitor and a pancreatic endocrine progenitor model. We provide evidence showing that pancreatic gastrin-expressing cells, found from embryonic day 12.5 until postnatal day 7, are derived from pancreatic Ptf1a(+) and neurogenin 3-expressing (Ngn3(+)) progenitors. Importantly, the majority of them coexpress glucagon, with 4% coexpressing insulin, indicating that they are a temporary subpopulation of both alpha and beta cells. Interestingly, Men1 disruption in both Ngn3 progenitors and beta and alpha cells resulted in the development of pancreatic gastrin-expressing tumors, suggesting that the latter developed from islet cells. Finally, we detected gastrin expression using three human cohorts with pancreatic endocrine tumors (pNETs) that have not been diagnosed as gastrinomas (in 9/34 pNETs from 6/14 patients with multiple endocrine neoplasia type 1, in 5/35 sporadic nonfunctioning pNETs, and in 2/20 sporadic insulinomas), consistent with observations made in mouse models. Our work provides insight into the histogenesis of pancreatic gastrin-expressing tumors.

  16. Utility of preoperative dynamic magnetic resonance imaging of the pancreas in diagnosing tumor-forming pancreatitis that mimics pancreatic cancer: report of a case.

    PubMed

    Kuroki, Tamotsu; Tajima, Yoshitsugu; Tsuneoka, Noritsugu; Adachi, Tomohiko; Kanematsu, Takashi

    2010-01-01

    The differential diagnosis of pancreatic carcinoma and tumor-forming pancreatitis remains difficult, and this situation can cause serious problems because the management and prognosis of these two focal pancreatic masses are entirely different. We herein report a case of tumor-forming pancreatitis that mimics pancreatic carcinoma in an 80-year-old woman. Computed tomography showed a solid mass in the head of the pancreas, and endoscopic retrograde cholangiopancreatography showed a complete obstruction of the main pancreatic duct in the head of the pancreas. Dynamic contrastenhanced magnetic resonance imaging (MRI) demonstrated a time-signal intensity curve (TIC) with a slow rise to a peak (1 min after the administration of the contrast material), followed by a slow decline at the pancreatic mass, indicating a fibrotic pancreas. Under the diagnosis of tumor-forming pancreatitis, the patient underwent a segmental pancreatectomy instead of a pancreaticoduodenectomy. The histopathology of the pancreatic mass was chronic pancreatitis without malignancy. The pancreatic TIC obtained from dynamiccontrast MRI can be helpful to differentiate tumor-forming pancreatitis from pancreatic carcinoma and to avoid any unnecessary major pancreatic surgery.

  17. Implications of Incidentally Discovered, Nonfunctioning Pancreatic Endocrine Tumors

    PubMed Central

    Haynes, Alex B.; Deshpande, Vikram; Ingkakul, Thun; Vagefi, Parsia A.; Szymonifka, Jackie; Thayer, Sarah P.; Ferrone, Cristina R.; Wargo, Jennifer A.; Warshaw, Andrew L.; Castillo, Carlos Fernández-del

    2011-01-01

    Objectives To describe the characteristics and outcomes after resection of incidentally discovered, nonfunctioning pancreatic endocrine tumors (PETs). Design Case series. Setting Academic hospital. Patients Consecutive patients with an incidentally identified, nonfunctioning PET resected from May 1, 1977, through July 31, 2009. Main Outcome Measures Operative morbidity and survival after resection. Results A total of 139 patients with median age of 56 years (range, 21–85 years) underwent resection; tumor size ranged from 0.4 to 17.0 cm, with median size of 3.0 cm. No perioperative deaths were reported. Sixty-one patients (43.9%) experienced a perioperative complication. Twenty-six tumors (18.7%) were classified as benign, 39 (28.1%) as malignant, and 72 (51.8%) as uncertain. We were unable to confidently classify 2 tumors due to lack of information regarding mitotic rate in the pathology report. Complete follow-up was available for 112 patients (80.6%) (median, 34.2 months). Five-year actuarial survival rates were 88.8% for patients with benign disease, 92.5% for patients with tumors of uncertain biology, and 49.8% for those with malignant tumors (P=.01). Late metastasis, tumor recurrence, or disease progression were seen in 1 patient (3.8%) with tumors initially classified as benign, 8 patients (11.1%) with uncertain tumors, and 15 patients (38.5%) with tumors classified as malignant (P<.001). Of the 39 patients with tumors 2 cm or smaller, 3 (7.7%) had late metastases or recurrence. When compared with patients with symptomatic, nonfunctioning PETs, no large difference was observed in tumor size, patient age, disease, or survival. Conclusions Incidentally detected, nonfunctioning PETs can display aggressive behavior, even when small. Although patients with malignant disease had diminished survival and increased rates of recurrence, benign histologic findings did not eliminate the possibility of progression. Patients with incidentally discovered, nonfunctioning

  18. Pancreatic Neuroendocrine Tumor in the Setting of Dorsal Agenesis of the Pancreas

    PubMed Central

    2016-01-01

    Dorsal agenesis of the pancreas (DAP) is an uncommon embryological abnormality where there is absence of the distal pancreas. DAP is mostly asymptomatic, but common presenting symptoms include diabetes mellitus, abdominal pain, pancreatitis, enlarged pancreatic head, and, in a few cases, polysplenia. MRCP and ERCP are the gold standard imaging techniques to demonstrate the absence of the dorsal pancreatic duct. The literature on the association of pancreatic neoplasia and DAP is limited. We present the case of a pancreatic neuroendocrine tumor in a patient with dorsal agenesis of the pancreas, with a review of the related literature. PMID:27738535

  19. Individualized 4-dimensional computed tomography proton treatment for pancreatic tumors

    PubMed Central

    Wang, Ning; Vassantachart, April; Mifflin, Rachel; Slater, Jerry D; Yang, Gary Y

    2017-01-01

    Background The goal of this study is to determine whether a phase or reconstruction of a 10-phase 4 dimensional computed tomography (4D CT) scan can be used as the primary planning scan for proton treatment of the pancreas, thus eliminating the need for second a slow CT or free breathing CT. Methods Ten patients with pancreatic adenocarcinoma were simulated with 4D CT and a proton treatment plan generated based upon one of three primary planning scans, the T0 phase, T50 phase or average reconstruction. These plans were then exported to each of the remaining phases of the 4D CT and the dose to 95% of the target (D95) calculated. Plans were deemed adequate if the D95 remained at 99% of the prescribed dose or greater. Results For the ten patients in this study anterior abdominal motion was found to range from 2–27 mm (mean 7.50±6.79 mm). For 9 of 10 patients the anterior abdominal motion was ≤8 mm and all three primary planning scans provided adequate target coverage, resulting in minimum D95 coverage per plan of T0_plan 99.7%, T50_plan 99.3% and AVE_plan 99%. However no plan provided adequate target coverage on the single patient with the largest anterior abdominal motion, 27 mm, and cranio-caudal motion, 20 mm, with minimum D95 values of T0_plan 96.3%, T50_plan 68%, and AVE_plan 68%. Conclusions The primary plans tested based up on the T0, T50 and average reconstructions provided adequate D95 coverage throughout the respiratory cycle as long as the anterior abdominal motion was ≤8 mm and can be considered for use as the primary proton planning scan. PMID:28890818

  20. Antibody against CD44s Inhibits Pancreatic Tumor Initiation and Post-Radiation Recurrence in Mice

    PubMed Central

    Li, Ling; Hao, Xinbao; Qin, Jun; Tang, Wenhua; He, Fengtian; Smith, Amber; Zhang, Min; Simeone, Diane M.; Qiao, Xiaotan T.; Chen, Zhi-Nan; Lawrence, Theodore S.; Xu, Liang

    2014-01-01

    Background & Aims CD44s is a surface marker of tumor-initiating cells (TICs); high tumor levels correlate with metastasis and recurrence, as well as poor outcomes of patients. Monoclonal antibodies against CD44s might eliminate TICs with minimal toxicity. This strategy is unclear for treatment of pancreatic cancer, and little is known about how anti-CD44s affect pancreatic cancer initiation or recurrence after radiotherapy. Methods 192 pairs of human pancreatic adenocarcinoma and adjacent non-tumor pancreatic tissues were collected from patients undergoing surgery. We measured CD44s levels in tissue samples and pancreatic cancer cell lines by immunohistochemistry, real-time PCR and immunoblot; levels were correlated with patient survival times. We studied the effects of anti-CD44s in mice with human pancreatic tumor xenografts, and used flow cytometry to determine effects on TICs. Changes in CD44s signaling were examined by real-time PCR, immunoblot, reporter assay, and in vitro tumorsphere formation assays. Results Levels of CD44s were significantly higher in pancreatic cancer than adjacent non-tumor tissues. Patients whose tumors expressed high levels of CD44s had a median survival of 10 months, compared to 43 months for those with low levels. Anti-CD44s reduced growth, metastasis, and post-radiation recurrence of pancreatic xenograft tumors in mice. The antibody reduced the number of TICs in cultured pancreatic cancer cells and in xenograft tumors, as well as their tumorigenicity. In cultured pancreatic cancer cell lines, anti-CD44s downregulated the stem cell self-renewal genes Nanog, Sox-2, and Rex-1 and inhibited STAT3-mediated cell proliferation and survival signaling. Conclusions The TIC marker CD44s is upregulated in human pancreatic tumors and associated with patient survival time. CD44s is required for initiation, growth, metastasis, and post-radiation recurrence of xenograft tumors in mice. Anti-CD44s eliminated bulk tumor cells as well as TICs from the

  1. Modulation of the leptin receptor mediates tumor growth and migration of pancreatic cancer cells.

    PubMed

    Mendonsa, Alisha M; Chalfant, Madeleine C; Gorden, Lee D; VanSaun, Michael N

    2015-01-01

    Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration.

  2. Modulation of the Leptin Receptor Mediates Tumor Growth and Migration of Pancreatic Cancer Cells

    PubMed Central

    Chalfant, Madeleine C.; Gorden, Lee D.

    2015-01-01

    Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration. PMID:25919692

  3. Pancreatic tumors in children and young adults with tuberous sclerosis complex.

    PubMed

    Koc, Gonca; Sugimoto, Sam; Kuperman, Rachel; Kammen, Bamidele F; Karakas, S Pinar

    2017-01-01

    Pancreatic neuroendocrine tumors are not included in the diagnostic criteria for tuberous sclerosis complex, although an association has been described. To investigate the association of pancreatic neuroendocrine tumor in children and young adults with tuberous sclerosis complex and define MRI characteristics of the tumor. We retrospectively evaluated the abdominal MRI scans of 55 children and young adults with tuberous sclerosis complex for the presence of a pancreatic mass. The scans were performed over a period of 7 years to monitor renal pathology. We obtained each patient's clinical history and treatment protocol from the hospital's electronic medical records. A solid pancreatic mass was identified in 5/55 (9%, 95% confidence interval [CI] 3-20%) patients (4 male) with a mean age of 12.6 years. Four of the lesions were located in the pancreatic tail and one in the pancreatic body. All of the lesions were solid, ovoid and well demarcated, with a mean diameter of 3.1 cm. The masses uniformly demonstrated T1 and T2 prolongation, but their diffusion behavior and post-contrast enhancement varied. The two surgically resected lesions were synaptophysin (+) non-functional pancreatic neuroendocrine tumors on pathology. Two of the patients who did not have surgery were treated with everolimus; one of the lesions has shown interval decrease in size and the other has remained stable. Pancreatic tumor is relatively common in children and young adults with tuberous sclerosis complex.

  4. Genetics of pancreatic neuroendocrine tumors: implications for the clinic

    PubMed Central

    Pea, Antonio; Hruban, Ralph H.; Wood, Laura D.

    2016-01-01

    Pancreatic neuroendocrine tumors (PanNETs) are a common and deadly neoplasm of the pancreas. Although the importance of genetic alterations in PanNETs has been known for many years, recent comprehensive sequencing studies have greatly expanded our knowledge of neuroendocrine tumorigenesis in the pancreas. These studies have identified specific cellular processes that are altered in PanNETs, highlighted alterations with prognostic implications, and pointed to pathways for targeted therapies. In this review, we will discuss the genetic alterations that play a key role in PanNET tumorigenesis, with a specific focus on those alterations with the potential to change the way patients with these neoplasms are diagnosed and treated. PMID:26413978

  5. Resection or cryosurgery relates with pancreatic tumor type: primary pancreatic cancer with previous non-pancreatic cancer or secondary metastatic cancer within the pancreas.

    PubMed

    Jin, Peng; Ji, Xiaoyan; Ren, He; Tang, Yong; Hao, Jihui

    2014-01-01

    We investigated the incidence of primary pancreatic cancer with previous non-pancreatic cancer (PPC) and secondary metastatic cancer within the pancreas (SMC) to elucidate the differential diagnosis and treatment of these lesions. The clinical data of 2539 patients with pancreatic mass in Tianjin Cancer Hospital from January 2000 to December 2012 were retrospectively analyzed. All of the 66 patients who showed double or multiple primary cancers or metastatic pancreatic malignancies were included into the PPC group or SMC group, respectively. In addition, PPC patients were compared with 570 patients suffering from pancreatic cancer (PC) alone. For the PPC group (n = 34), the most common previous non-pancreatic cancers were gastric cancer, breast cancer, and thyroid cancer. For the SMC group (n = 32), the most common metastatic tumors were lung cancer, renal cell carcinoma (RCC), and gastric cancer. Multivariate analysis identified age (OR = 1.099; 95% CI, 1.007-1.199), previous tumor type (OR = 1.164; 95% CI, 1.046-1.296), and time interval between two tumors (OR = 1.021; 95% CI, 1.003-1.039) as significant indicators. Significantly better survival times were observed after resection than after cryosurgery in the PPC group (p < 0.001) but not in the SMC group (p = 0.670). Overall, primary pancreatic cancers are as common as metastasis to the pancreas in patients with a previous cancer. A longer time interval between two tumors indicates a higher possibility that a new pancreatic cancer will occur. Some cancers (particularly RCC) are more likely to metastasize to the pancreas than other cancers. For metastatic cancers, cryosurgery is as effective as resection as a treatment option. Copyright © 2013 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  6. Somatostatin analog octreotide LAR in gastro-entero-pancreatic tumors.

    PubMed

    Oberg, Kjell

    2009-05-01

    Neuroendocrine tumors (NETs) are considered to be rare but, during the last two decades, their incidence and prevalence has considerably increased in gastro-entero-pancreatic (GEP) NETs. Most GEP-NETs express somatostatin receptors, which could be targets for treatment. The development of somatostatin analogs for treatment of functioning NETs was a revolution in the treatment of these patients and is still a cornerstone for managing hormone-related clinical symptoms. Furthermore, somatostatin analogs have also demonstrated an anti-tumor effect, with stabilization of tumor growth over long periods of time. The development of a long-acting formulation of octreotide long-acting release (LAR) significantly improved the quality of life for patients with functioning NETs in terms of necessitating only monthly injections. The side effects are few and easily manageable. In the future, somatostatin analogs will continue to be a major treatment option for functioning NETs, but will be combined with other biologicals, such as a-interferons, mTOR inhibitors and VEGF inhibitors. A new multireceptor somatostatin analog, SOM230 (pasireotide), as well as chimeric molecules, such as dopastatin (a combination of a somatostatin analogue plus a dopamine agonist), will come into the clinical management of GEP-NETs.

  7. Feasibility of Electromagnetic Transponder Use to Monitor Inter- and Intrafractional Motion in Locally Advanced Pancreatic Cancer Patients

    SciTech Connect

    Shinohara, Eric T.; Kassaee, Alireza; Mitra, Nandita; Vapiwala, Neha; Plastaras, John P.; Drebin, Jeff; Wan, Fei; Metz, James M.

    2012-06-01

    Purpose: The primary objective of this study was to determine the feasibility of electromagnetic transponder implantation in patients with locally advanced unresectable pancreatic cancer. Secondarily, the use of transponders to monitor inter- and intrafractional motion, and the efficacy of breath holding for limiting target motion, were examined. Methods and Materials: During routine screening laparoscopy, 5 patients without metastatic disease were implanted with transponders peri-tumorally. The Calypso System's localization and tracking modes were used to monitor inter- and intrafractional motion, respectively. Intrafractional motion, with and without breath holding, was also examined using Calypso tracking mode. Results: Transponder implantation was well tolerated in all patients, with minimal migration, aside from 1 patient who expulsed a single transponder. Interfractional motion based on mean shifts from setup using tattoos/orthogonal imaging to transponder based localization from 164 treatments was significant in all dimensions. Mean shift (in millimeters), followed by the standard deviation and p value, were as follows: X-axis: 4.5 mm (1.0, p = 0.01); Y axis: 6.4 mm (1.9, p = 0.03); and Z-axis 3.9 mm (0.6, p = 0.002). Mean intrafractional motion was also found to be significant in all directions: superior, 7.2 mm (0.9, p = 0.01); inferior, 11.9 mm (0.9, p < 0.01); anterior: 4.9 mm (0.5, p = 0.01); posterior, 2.9 mm (0.5, p = 0.02); left, 2.2 mm (0.4, p = 0.02); and right, 3.1 mm (0.6, p = 0.04). Breath holding during treatment significantly decreased tumor motion in all directions. Conclusions: Electromagnetic transponder implantation appears to be safe and effective for monitoring inter- and intrafractional motion. Based on these results a larger clinical trial is underway.

  8. MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.

    PubMed

    Cros, J; Hentic, O; Rebours, V; Zappa, M; Gille, N; Theou-Anton, N; Vernerey, D; Maire, F; Lévy, P; Bedossa, P; Paradis, V; Hammel, P; Ruszniewski, P; Couvelard, A

    2016-08-01

    Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O(6)-methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58years (27-84)) with grade 1 WDPNET (n=6) or 2 (n=36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P=0.04) and better progression-free survival (PFS) (HR=0.35 (0.15-0.81), P=0.01). Disease control rate at 18months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR=0.37 (0.29-1.08), P=0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

  9. Diaphragm motion characterization using chest motion data for biomechanics-based lung tumor tracking during EBRT

    NASA Astrophysics Data System (ADS)

    Karami, Elham; Gaede, Stewart; Lee, Ting-Yim; Samani, Abbas

    2016-03-01

    Despite recent advances in image-guided interventions, lung cancer External Beam Radiation Therapy (EBRT) is still very challenging due to respiration induced tumor motion. Among various proposed methods of tumor motion compensation, real-time tumor tracking is known to be one of the most effective solutions as it allows for maximum normal tissue sparing, less overall radiation exposure and a shorter treatment session. As such, we propose a biomechanics-based real-time tumor tracking method for effective lung cancer radiotherapy. In the proposed algorithm, the required boundary conditions for the lung Finite Element model, including diaphragm motion, are obtained using the chest surface motion as a surrogate signal. The primary objective of this paper is to demonstrate the feasibility of developing a function which is capable of inputting the chest surface motion data and outputting the diaphragm motion in real-time. For this purpose, after quantifying the diaphragm motion with a Principal Component Analysis (PCA) model, correlation coefficient between the model parameters of diaphragm motion and chest motion data was obtained through Partial Least Squares Regression (PLSR). Preliminary results obtained in this study indicate that the PCA coefficients representing the diaphragm motion can be obtained through chest surface motion tracking with high accuracy.

  10. Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma.

    PubMed

    O'Connor, Kate; Li-Chang, Hector H; Kalloger, Steven E; Peixoto, Renata D; Webber, Douglas L; Owen, David A; Driman, David K; Kirsch, Richard; Serra, Stefano; Scudamore, Charles H; Renouf, Daniel J; Schaeffer, David F

    2015-04-01

    Tumor budding is a well-established adverse prognostic factor in colorectal cancer. However, the significance and diagnostic reproducibility of budding in pancreatic carcinoma requires further study. We aimed to assess the prognostic significance of tumor budding in pancreatic ductal adenocarcinoma, determine its relationship with other clinicopathologic features, and assess interobserver variability in its diagnosis. Tumor budding was assessed in 192 archival cases of pancreatic ductal adenocarcinoma using hematoxylin and eosin (H&E) sections; tumor buds were defined as single cells or nonglandular clusters composed of <5 cells. The presence of budding was determined through assessment of all tumor-containing slides, and associations with clinicopathologic features and outcomes were analyzed. Six gastrointestinal pathologists participated in an interobserver variability study of 120 images of consecutive tumor slides stained with H&E and cytokeratin. Budding was present in 168 of 192 cases and was associated with decreased overall survival (P=0.001). On multivariable analysis, tumor budding was prognostically significantly independent of stage, grade, tumor size, nodal status, lymphovascular invasion, and perineural invasion. There was substantial agreement among pathologists in assessing the presence of tumor budding using both H&E (K=0.63) and cytokeratin (K=0.63) stains. The presence of tumor budding is an independent adverse prognostic factor in pancreatic ductal carcinoma. The assessment of budding with H&E is reliable and could be used to better risk stratify patients with pancreatic ductal adenocarcinoma.

  11. A triple combination of atorvastatin, celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors.

    PubMed

    Ding, Ning; Cui, Xiao-Xing; Gao, Zhi; Huang, Huarong; Wei, Xingchuan; Du, Zhiyun; Lin, Yong; Shih, Weichung Joe; Rabson, Arnold B; Conney, Allan H; Hu, Chunhong; Zheng, Xi

    2014-06-01

    Because K-Ras mutation and cyclooxygenase-2 (COX-2) overexpression are hallmarks of majority of pancreatic cancer patients, an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets, should be considered. In the present study, we assessed the effects of atorvastatin (Lipitor), celecoxib (Celebrex) and tipifarnib (Zarnestra) on the growth of human pancreatic cancer. In the in vitro studies, we found that treatment of human pancreatic tumor cells with a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs. We also found that treatment of Panc-1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1/2 and Akt. In an animal model of xenograft tumors in severe combined immunodeficient (SCID) mice, we found that daily i.p. injections of a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs. The results of our study indicate that a combination of atorvastatin, celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer.

  12. Molecular Markers for Novel Therapeutic Strategies in Pancreatic Endocrine Tumors

    PubMed Central

    Gilbert, Judith A.; Adhikari, Laura J.; Lloyd, Ricardo V.; Halfdanarson, Thorvardur R.; Muders, Michael H.; Ames, Matthew M.

    2012-01-01

    Objectives Pancreatic endocrine tumors (PETs) share numerous features with gastrointestinal neuroendocrine (carcinoid) tumors. Targets of novel therapeutic strategies previously assessed in carcinoid tumors were analyzed in PETs (44 cases). Methods Activating mutations in EGFR, KIT, and PDGFRA, and non-response mutations in KRAS, were evaluated. Copy number of EGFR and HER-2/neu was quantified by fluorescence in situ hybridization. Expression of EGFR, PDGFRA, VEGFR1, TGFBR1, Hsp90, SSTR2A, SSTR5, IGF1R, mTOR, and MGMT was measured immunohistochemically. Results Elevated EGFR copy number was found in 38% of cases, but no KRAS non-response mutations. VEGFR1, TGFBR1, PDGFRA, SSTR5, SSTR2A, and IGF1R exhibited the highest levels of expression in the largest percentages of PETs. Anticancer drugs BMS-754807 (selective for IGF1R/IR), 17-(allylamino)-17-demethoxygeldanamycin (17-AAG, targeting Hsp90), and axitinib (directed toward VEGFR1–3/PDGFRA-B/KIT) induced growth inhibition of human QGP-1 PET cells with IC50 values (nM) of 273, 723, and 743, respectively. At growth-inhibiting concentrations, BMS-754807 inhibited IGF1R phosphorylation; 17-AAG induced loss of EGFR, IGF1R, and VEGFR2; and axitinib increased p21Waf1/Cip1(CDKN1A) expression without inhibiting VEGFR2 phosphorylation. Conclusions Results encourage further research into multi-drug strategies incorporating inhibitors targeting IGF1R or Hsp90 and into studies of axitinib combined with conventional chemotherapeutics toxic to tumor cells in persistent growth arrest. PMID:23211371

  13. A p53 Super-tumor Suppressor Reveals a Tumor Suppressive p53-Ptpn14-Yap Axis in Pancreatic Cancer.

    PubMed

    Mello, Stephano S; Valente, Liz J; Raj, Nitin; Seoane, Jose A; Flowers, Brittany M; McClendon, Jacob; Bieging-Rolett, Kathryn T; Lee, Jonghyeob; Ivanochko, Danton; Kozak, Margaret M; Chang, Daniel T; Longacre, Teri A; Koong, Albert C; Arrowsmith, Cheryl H; Kim, Seung K; Vogel, Hannes; Wood, Laura D; Hruban, Ralph H; Curtis, Christina; Attardi, Laura D

    2017-10-09

    The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p53(53,54) TAD2 mutant behaves as a "super-tumor suppressor," with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53. We show that p53 deficiency promotes Yap signaling and that PTPN14 and TP53 mutations are mutually exclusive in human cancers. These studies uncover a p53-Ptpn14-Yap pathway that is integral to p53-mediated tumor suppression. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  14. Molecular pathogenesis and targeted therapy of sporadic pancreatic neuroendocrine tumors.

    PubMed

    Capurso, Gabriele; Archibugi, Livia; Delle Fave, Gianfranco

    2015-08-01

    Over the past few years, knowledge regarding the molecular pathology of sporadic pancreatic neuroendocrine tumors (PNETs) has increased substantially, and a number of targeted agents have been tested in clinical trials in this tumor type. For some of these agents there is a strong biological rationale. Among them, the mammalian target of rapamycin inhibitor Everolimus and the antiangiogenic agent Sunitinib have both been approved for the treatment of PNETs. However, there is lack of knowledge regarding biomarkers able to predict their efficacy, and mechanisms of resistance. Other angiogenesis inhibitors, such as Pazopanib, inhibitors of Src, Hedgehog or of PI3K might all be useful in association or sequence with approved agents. On the other hand, the clinical significance, and potential for treatment of the most common mutations occurring in sporadic PNETs, in the MEN-1 gene and in ATRX and DAXX, remains uncertain. The present paper reviews the main molecular changes occurring in PNETs and how they might be linked with treatment options.

  15. Pancreatic Neuroendocrine Tumors: Computed Tomography Enhancement, But Not Histological Grade, Correlates With Tumor Aggression.

    PubMed

    Yano, Motoyo; Misra, Sunil; Carpenter, Danielle H; Salter, Amber; Hildebolt, Charles F

    2017-09-19

    The aims of this study were to assess computed tomography enhancement of pancreatic neuroendocrine tumors (NETs), determine correlation with histological vascularity and fibrosis, and identify a biomarker for tumor aggression. The arterial and venous enhancement of NET was calculated on computed tomography for 56 patients. Tumor size and vascularity/fibrosis were assessed. Tumor aggression was grouped by World Health Organization and Hochwald grade and the presence of metastases. Variables were assessed for correlation. Groups were compared using t test/Wilcoxon rank sum test. Arterial enhancement and dynamic washout (r = 0.35, P = 0.02; r = 0.34, P = 0.02, respectively) correlate with vascularity. There is inverse correlation between vascularity and fibrosis (r = -0.62, P < 0.001), but no correlation between enhancement and fibrosis. Metastatic NET had less arterial (mean, -2 [standard deviationi {SD}, 27.1] Hounsfield unit [HU]; 35.7 [SD, 57.5] HU; P = 0.01) and venous (12.6 [SD, 14.4] HU; 29.2 [SD, 38.3] HU; P = 0.04) enhancement and less washout (8.5 [SD, 18.5] HU; 26.8 [SD, 30] HU, P = 0.02) compared with nonmetastatic NET. These differences were not present when comparing by tumor grade. Arterial hypoenhancement was the only significant predictor of metastases. Aggressive tumors, as determined by metastases, but not histological grade, enhance less than nonmetastatic tumors.

  16. Metformin with everolimus and octreotide in pancreatic neuroendocrine tumor patients with diabetes.

    PubMed

    Pusceddu, Sara; Buzzoni, Roberto; Vernieri, Claudio; Concas, Laura; Marceglia, Sara; Giacomelli, Luca; Milione, Massimo; Leuzzi, Livia; Femia, Daniela; Formisano, Barbara; Mazzaferro, Vincenzo; de Braud, Filippo

    2016-05-01

    A bidirectional relationship seems to exist between diabetes mellitus and development of pancreatic tumors. Metformin, the most widely used drug in the treatment of Type 2 diabetes mellitus, has recently emerged as a potentially active agent in cancer chemoprevention and treatment. In this article, we discuss the potential correlation between glycemic status, administration of antiglycemic treatments, such as metformin or insulin, and prognosis of pancreatic neuroendocrine tumors patients treated with everolimus and octreotide, on the basis of existing evidence and our experience.

  17. Acycloguanosyl 5'-thymidyltriphosphate, a thymidine analogue prodrug activated by telomerase, reduces pancreatic tumor growth in mice.

    PubMed

    Polvani, Simone; Calamante, Massimo; Foresta, Valeria; Ceni, Elisabetta; Mordini, Alessandro; Quattrone, Alessandro; D'Amico, Massimo; Luchinat, Claudio; Bertini, Ivano; Galli, Andrea

    2011-02-01

    Gemcitabine is the standard of care for metastatic and nonresectable pancreatic tumors. Phase II and III trials have not demonstrated efficacy of recently developed reagents, compared with gemcitabine alone; new chemotherapic agents are needed. Ninety percent of pancreatic tumors have telomerase activity, and expression correlates with tumor stage. We developed a thymidine analogue prodrug, acycloguanosyl 5'-thymidyltriphosphate (ACV-TP-T), that is metabolized by telomerase and releases the active form of acyclovir. We investigated the antitumor efficacy of ACV-TP-T in vitro and in vivo. We evaluated proliferation and apoptosis of human pancreatic cancer cells (PANC-1, MiaPaca2, BxPc3, PL45, and Su.86.86) incubated with ACV-TP-T. The presence of ACV-TP-T and its metabolite inside the cells were analyzed by mass spectrometry. In vivo efficacy was evaluated in nude mice carrying PANC-1 or MiaPaca2 pancreatic xenograft tumors. The prodrug of ACV-TP-T was actively metabolized inside pancreatic cancer cells into the activated form of acyclovir; proliferation was reduced, apoptosis was increased, and the cell cycle was altered in pancreatic cancer incubated with ACV-TP-T, compared with controls. Administration of ACV-TP-T to mice reduced growth, increased apoptosis, and reduced proliferation and vascularization of pancreatic xenograft tumors. ACV-TP-T, a thymidine analogue that is metabolized by telomerase and releases the active form of acyclovir, reduces proliferation and induces apoptosis of human pancreatic cancer cell lines in vitro and pancreatic xenograft tumors in mice. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

  18. Systematic comparison of sporadic and syndromic pancreatic islet cell tumors.

    PubMed

    Erlic, Zoran; Ploeckinger, Ursula; Cascon, Alberto; Hoffmann, Michael M; von Duecker, Laura; Winter, Aurelia; Kammel, Gerit; Bacher, Janina; Sullivan, Maren; Isermann, Berend; Fischer, Lars; Raffel, Andreas; Knoefel, Wolfram Trudo; Schott, Matthias; Baumann, Tobias; Schaefer, Oliver; Keck, Tobias; Baum, Richard P; Milos, Ioana; Muresan, Mihaela; Peczkowska, Mariola; Januszewicz, Andrzej; Cupisti, Kenko; Tönjes, Anke; Fasshauer, Mathias; Langrehr, Jan; von Wussow, Peter; Agaimy, Abbas; Schlimok, Günter; Lamberts, Regina; Wiech, Thorsten; Schmid, Kurt Werner; Weber, Alexander; Nunez, Mercedes; Robledo, Mercedes; Eng, Charis; Neumann, Hartmut P H

    2010-12-01

    Pancreatic islet cell tumors (ICTs) occur as sporadic neoplasias or as a manifestation of multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau disease (VHL). Molecular classification of ICTs is mandatory for timely diagnosis and surveillance. Systematic comparison of VHL-ICTs and sporadic ICTs has been lacking. Our registry-based approaches used the German NET-Registry with 259 patients with neuroendocrine tumors (NETs), who were primarily diagnosed with NETs, and the German VHL-Registry with 485 molecular genetically confirmed patients who had undergone magnetic resonance imaging or computed tomography of the abdomen. All patients provided blood DNA for testing of the MEN1 and VHL genes for intragenic mutations and large deletions. In the NET-Registry, 9/101 patients (8.9%) with ICTs had germline mutations, 8 in MEN1 and 1 in VHL. In the VHL-Registry, prevalence of NETs was 52/487 (10.6%), and all were ICTs. Interestingly, of those with VHL p.R167W, 47% developed ICTs, compared to 2% of those with p.Y98H. In total, there were 92 truly sporadic, i.e. mutation-negative ICT patients. Comparing these with the 53 VHL-ICT patients, the statistically significant differences were predominance of female gender (P=0.01), multifocal ICTs (P=0.0029), and lower malignancy rate (P<0.001) in VHL-ICTs compared to sporadic cases. VHL was prevalent in <0.5% of NETs, while NETs occur in ∼10% of VHL, virtually exclusively as ICTs, which are rarely the first presentation. Patients with NETs should not be subjected to genetic testing of the VHL gene, unless they have multifocal ICTs, other VHL-associated tumors, and/or a family history for VHL.

  19. Impact of APE1/Ref-1 Redox Inhibition on Pancreatic Tumor Growth

    PubMed Central

    Fishel, Melissa L.; Jiang, Yanlin; Rajeshkumar, N. V.; Scandura, Glenda; Sinn, Anthony L.; He, Ying; Shen, Changyu; Jones, David R.; Pollok, Karen E.; Ivan, Mircea; Maitra, Anirban; Kelley, Mark R.

    2011-01-01

    Pancreatic cancer is an especially deadly form of cancer with a survival rate <2%. Pancreatic cancers respond poorly to existing chemotherapeutic agents and radiation, and progress for the treatment of pancreatic cancer remains elusive. To address this unmet medical need, a better understanding of critical pathways and molecular mechanisms involved in pancreatic tumor development, progression and resistance to traditional therapy is therefore critical. Reduction-oxidation (redox) signaling systems are emerging as important targets in pancreatic cancer. AP endonuclease1/ Redox effector factor 1 (APE1/Ref-1) is upregulated in human pancreatic cancer cells and modulation of its redox activity blocks the proliferation and migration of pancreatic cancer cells as well as pancreatic cancer-associated endothelial cells (PCECs) in vitro. Modulation of APE1/Ref-1 using a specific inhibitor of APE1/Ref-1’s redox function, E3330 leads to a decrease in transcription factor activity for NFκB, AP-1, and HIF1 in vitro. This study aims to further establish the redox signaling protein APE1/Ref-1 as a molecular target in pancreatic cancer. Here, we show that inhibition of APE1/Ref-1 via E3330 results in tumor growth inhibition in cell lines as well as pancreatic cancer xenograft models in mice. Pharmacokinetic (PK) studies also demonstrate that E3330 attains >10 μM blood concentrations and is detectable in tumor xenografts. Through inhibition of APE1/Ref-1, the activity of NFκB, AP-1, and HIF1α which are key transcriptional regulators involved in survival, invasion and metastasis is blocked. These data indicate that E3330, inhibitor of APE1/Ref-1, has potential in pancreatic cancer and clinical investigation of APE1/Ref-1 molecular target is warranted. PMID:21700832

  20. WE-G-18C-06: Is Diaphragm Motion a Good Surrogate for Liver Tumor Motion?

    SciTech Connect

    Yang, J; Cai, J; Zheng, C; Czito, B; Palta, M; Yin, F; Wang, H; Bashir, M

    2014-06-15

    Purpose: To investigate whether diaphragm motion is a good surrogate for liver tumor motion by comparing their motion trajectories obtained from cine-MRI. Methods: Fourteen patients with hepatocellular carcinoma (10/14) or liver metastases (4/14) undergoing radiation therapy were included in this study. All patients underwent single-slice 2D cine-MRI simulations across the center of the tumor in three orthogonal planes. Tumor and diaphragm motion trajectories in the superior-inferior (SI), anteriorposterior (AP), and medial-lateral (ML) directions were obtained using the normalized cross-correlation based tracking technique. Agreement between tumor and diaphragm motions was assessed by calculating the phase difference percentage (PDP), intra-class correlation coefficient (ICC), Bland-Altman analysis (Diffs) and paired t-test. The distance (D) between tumor and tracked diaphragm area was analyzed to understand its impact on the correlation between tumor and diaphragm motions. Results: Of all patients, the means (±standard deviations) of PDP were 7.1 (±1.1)%, 4.5 (±0.5)% and 17.5 (±4.5)% in the SI, AP and ML directions, respectively. The means of ICC were 0.98 (±0.02), 0.97 (±0.02), and 0.08 (±0.06) in the SI, AP and ML directions, respectively. The Diffs were 2.8 (±1.4) mm, 2.4 (±1.1) mm, and 2.2 (±0.5) mm in the SI, AP and ML directions, respectively. The p-values derived from the paired t-test were < 0.02 in SI and AP directions, whereas were > 0.58 in ML direction primarily due to the small motion in ML direction. Tumor and diaphragmatic motion had high concordance when the distance between the tumor and tracked diaphragm areas was small. Conclusion: Preliminary results showed that liver tumor motion had good correlations with diaphragm motion in the SI and AP directions, indicating diaphragm motion in the SI and AP directions could potentially be a reliable surrogate for liver tumor motion. NIH (1R21CA165384-01A1), Golfers Against Cancer (GAC

  1. Differentiation of solid pancreatic tumors by using dynamic contrast-enhanced MRI

    NASA Astrophysics Data System (ADS)

    Choi, Seung Joon; Kim, Hyung Sik; Park, Hyunjin

    2014-01-01

    Distinguishing among different solid pancreatic tumor types, pancreatic ductal adenocarcinomas, neuroendocrine tumors (NETs), and solid pseudopapillary tumors (SPTs) is important, as the treatment options are vastly different. This study compared characteristics of solid pancreatic tumors by using dynamic contrast enhanced magnetic resonance imaging (MRI). Fifty patients underwent MR imaging of pancreatic masses with a histopathology that was later confirmed as an adenocarcinoma (n = 27), a NET (n = 16), and a SPT (n = 7). For qualitative analysis, two reviewers evaluated the morphologic features of the tumors: locations, margins, shapes, contained products, pancreatic ductal dilatation, and grade of signal intensity (SI). For the quantitative analysis, all phases of the MR images were co-registered using proprietary image registration software; thus, a region of interest (ROI) defined on one phase could be re-applied in other phases. The following four ratios were considered: tumor-to-uninvolved pancreas SI ratio, percent SI change, tumor-touninvolved pancreas enhancement index, and arterial-to-delayed washout rate. The areas under the receiver operating characteristic (ROC) curves were assessed for the four ratios. Adenocarcinomas had ill-defined margins, irregular shapes, and ductal dilatation compared with NETs and SPTs (P < 0.001). The tumor-to-uninvolved pancreas ratio on all dynamic phases was significantly higher for NETs than for both adenocarcinomas and SPTs (P < 0.05). Percentage SI changes of pancreatic tumors on the pancreatic and the portal venous phases were significantly higher for NETs than for both adenocarcinomas and SPTs (P < 0.05). A significant difference between NETs and adenocarcinomas was also found with respect to the tumor-to-uninvolved pancreas enhancement index and arterial-to-delayed washout rate. The percentage SI changes in the pancreatic phase and the arterial-to-delayed washout rate best distinguished between adenocarcinomas and

  2. Pancreatic ducts as an important route of tumor extension for acinar cell carcinoma of the pancreas.

    PubMed

    Ban, Daisuke; Shimada, Kazuaki; Sekine, Shigeki; Sakamoto, Yoshihiro; Kosuge, Tomoo; Kanai, Yae; Hiraoka, Nobuyoshi

    2010-07-01

    Acinar cell carcinoma (ACC) of the pancreas is very rare, which usually grows expansively. Recently, a variant of ACC with predominant growth in the pancreatic ducts has been proposed, and is speculated to have potentially less aggressive behavior. The aim of this study was to investigate how the pancreatic duct system is related to the growth and extension of ACC. We reviewed the detailed gross and histologic features of 13 cases of ACC, of which 7 (54%) showed intraductal polypoid growth (IPG) of the tumor in the large pancreatic ducts with a mean IPG length of 24.8 mm. Tumors with IPG were found to spread characteristically along the pancreatic ducts as extending polypoid projections, filling the ducts and destroying the duct walls, although tumors did not tend to extend beyond the pancreatic parenchyma. Comparison of the clinicopathologic characteristics showed that ACC with IPG had less infiltrative features including lymphatic, venous, and neural invasion, formation of tumor thrombus in the portal vein, nodal metastasis, and invasion beyond the pancreas to the surrounding organs; death in only 1 case (14%) of ACC with IPG was the result of ACC itself. In contrast, ACC without IPG frequently showed more infiltrative growth, and was the cause of death in 50% of patients with this type of tumor. Intraductal dissemination of ACC in pancreatic ducts was proven in 1 case of ACC with IPG. These findings suggest that a significant proportion of ACC shows IPG, which is potentially linked to less aggressive clinicopathologic characteristics.

  3. Prognostic Value of Somatostatin Receptor Subtypes in Pancreatic Neuroendocrine Tumors.

    PubMed

    Song, Ki Byung; Kim, Song Cheol; Kim, Ji Hun; Seo, Dong-Wan; Hong, Seung-Mo; Park, Kwang-Min; Hwang, Dae Wook; Lee, Jae Hoon; Lee, Young-Joo

    2016-02-01

    Studies on the expression of somatostatin receptor (SSTR) subtypes in pancreatic neuroendocrine tumors (PNETs) are rare. The aim of this study was to determine the expression of the SSTR subtypes via immunohistochemistry analyses and assess the correlation between SSTR subtype expression and prognosis. We examined 199 patients with PNET who underwent surgical resection between January 1995 and December 2010 at the Asan Medical Center. For all cases, medical records, including demographic data, clinical symptoms, radiological findings, postoperative treatment outcomes, and expression of SSTR subtypes, were carefully reviewed. In total, 162 (81.4%) PNETs expressed more than 1 SSTR subtype. Functioning PNET expressed significantly more SSTR subtypes, compared to nonfunctioning PNET. The SSTR2(+) and SSTR5(+) groups had better prognosis than the SSTR2(-) (P = 0.009) and SSTR5(-) groups (P = 0.03), respectively. In the grade 2 PNET of 2010 World Health Organization classification, the SSTR(+) group had better prognosis than SSTR(-) group. The expression of SSTR 2 and 5 were related with good prognosis of PNET. In World Health Organization grade 2 PNET, the SSTR(+) group had better prognosis than SSTR(-) group. The SSTR expression(+) by immunohistochemistry might be related with good prognosis of the patients with surgically resected PNET.

  4. Circulating tumor cells in pancreatic cancer patients: Enrichment and cultivation

    PubMed Central

    Bobek, Vladimir; Gurlich, Robert; Eliasova, Petra; Kolostova, Katarina

    2014-01-01

    AIM: To investigate the feasibility of separation and cultivation of circulating tumor cells (CTCs) in pancreatic cancer (PaC) using a filtration device. METHODS: In total, 24 PaC patients who were candidates for surgical treatment were enrolled into the study. Peripheral blood samples were collected before an indicated surgery. For each patient, approximately 8 mL of venous blood was drawn from the antecubital veins. A new size-based separation MetaCell® technology was used for enrichment and cultivation of CTCs in vitro. (Separated CTCs were cultured on a membrane in FBS enriched RPMI media and observed by inverted microscope. The cultured cells were analyzed by means of histochemistry and immunohistochemistry using the specific antibodies to identify the cell origin. RESULTS: CTCs were detected in 16 patients (66.7%) of the 24 evaluable patients. The CTC positivity did not reflect the disease stage, tumor size, or lymph node involvement. The same percentage of CTC positivity was observed in the metastatic and non-metastatic patients (66.7% vs 66.7%). We report a successful isolation of CTCs in PaC patients capturing proliferating cells. The cells were captured by a capillary action driven size-based filtration approach that enabled cells cultures from the viable CTCs to be unaffected by any antibodies or lysing solutions. The captured cancer cells displayed plasticity which enabled some cells to invade the separating membrane. Further, the cancer cells in the “bottom fraction”, may represent a more invasive CTC-fraction. The CTCs were cultured in vitro for further downstream applications. CONCLUSION: The presented size-based filtration method enables culture of CTCs in vitro for possible downstream applications. PMID:25493031

  5. Pancreatic neuroendocrine tumors: correlation between histogram analysis of apparent diffusion coefficient maps and tumor grade.

    PubMed

    Pereira, Jose Antonio Sousa; Rosado, Elsa; Bali, Maria; Metens, Thierry; Chao, Shih-Li

    2015-10-01

    To explore the role of histogram analysis of apparent diffusion coefficient (ADC) MRI maps based on entire tumor volume data in determining pancreatic neuroendocrine tumor (PNT) grade. Retrospective evaluation of 22 patients with PNTs included low-grade (G1; n = 15), intermediate-grade (G2; n = 4), and high-grade (G3; n = 3) tumors. Regions of interest containing the lesion were drawn on every section of the ADC map containing the tumor and summated to obtain histograms for entire tumor volume. Calculated histographic parameters included mean ADC (mADC), 5th percentile ADC, 10th percentile ADC, 25th percentile ADC, 50th percentile ADC, 75th percentile ADC (ADC75), 90th percentile ADC (ADC90) and 95th percentile ADC (ADC95), skewness and kurtosis. Histogram parameters were correlated with tumor grade by repeated measures analysis of variance with Tukey-Kramer post hoc comparisons. The mADC, ADC75, ADC90, and ADC95 were significantly higher in G1 tumors (1283 ± 267; 1404 ± 300; 1495 ± 318; 1562 ± 347 × 10(-6) mm(2)/s) compared to G2 (892 ± 390; 952 ± 381; 1036 ± 384; 1072 ± 374 × 10(-6) mm(2)/s) and to G3 tumors (733 ± 225; 864 ± 284; 1008 ± 288; 1152 ± 192 × 10(-6) mm(2)/s) (p value <0.05). Skewness and kurtosis were significantly different between G1 (0.041 ± 0.466; 2.802 ± 0.679) and G3 (1.01 ± 1.140; 5.963 ± 4.008) tumors (p value <0.05). Tumor volume (mL) was significantly higher on G3 (55 ± 15.7) compared to G1 (1.9 ± 2.7) and G2 (4.5 ± 3.6) tumors (p value <0.05). In this small sample size, we did not detect statistically significant parameters between G2 (n = 4) and G3 (n = 3) tumors. Histographic analysis of ADC maps on the basis of the entire tumor volume can be useful in differentiating histologic grades of PNTs.

  6. Molecular pathology of pancreatic cancer: in quest of tumor suppressor genes.

    PubMed

    Furukawa, Toru; Horii, Akira

    2004-04-01

    To find molecular clues useful for early detection and effective therapy for pancreatic cancer, we first carried out genomic analysis by means of comparative genomic hybridization and micro-satellite analysis. We found very complicated molecular alterations in multiple chromosomal regions, including 1p, 6q, 9p, 12q, 17p, 18q, and 21q for losses and 8q and 20q for gains. These diverse changes are very characteristic of pancreatic cancer, and from this information, we developed a method for detecting the aberrant copy numbers of specific chromosomal regions by fluorescence in situ hybridization in cells collected from pancreatic juice for early diagnosis of pancreatic neoplasms. The regions of losses suggest the existence of tumor suppressor genes (TSGs). We identified DUSP6/MKP-3 at 12q21-q22 as a strong candidate TSG; it showed epigenetic inactivation in some fractions of invasive pancreatic cancer and growth suppression and apoptosis by overexpression in vitro. To determine the pathologic roles of 18q, we introduced a normal copy of chromosome 18 into cultured pancreatic cancer cells. The introduction induced marked suppressions of tumor formation and metastasis formation in vivo. We continue work to more completely understand the complex molecular mechanisms of pancreatic carcinogenesis and to apply the information gained to the clinical treatment of pancreatic cancer.

  7. Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth

    PubMed Central

    Shukla, Surendra K.; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua; Goode, Gennifer; King, Ryan; Mishra, Anusha; Rai, Ibha; Nagarajan, Sangeetha; Chaika, Nina V.; Yu, Fang; Singh, Pankaj K.

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models. PMID:26510913

  8. Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth.

    PubMed

    Shukla, Surendra K; Dasgupta, Aneesha; Mehla, Kamiya; Gunda, Venugopal; Vernucci, Enza; Souchek, Joshua; Goode, Gennifer; King, Ryan; Mishra, Anusha; Rai, Ibha; Nagarajan, Sangeetha; Chaika, Nina V; Yu, Fang; Singh, Pankaj K

    2015-12-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models.

  9. In vivo localized harmonic motion imaging of VX2 tumors

    NASA Astrophysics Data System (ADS)

    Curiel, Laura; Hynynen, Kullervo

    2012-10-01

    We evaluated the feasibility of localized harmonic motion (LHM) imaging for tumor detection in vivo. LHM was induced using a single-element focused ultrasound (FUS) transducer (80 mm focal, 100 mm diameter, 1.54 MHz) and a separate transducer (5 kHz PRF, 5 MHz) was used to track motion by cross-correlating RF signals. A scan was performed with the transducers assembly and LHM was induced 5 times per location. Images were formed averaging the calculated LHM amplitudes. Ten New Zealand rabbits had VX2 tumors implanted on their thighs. Tumors were located using Magnetic resonance images and LHM images were obtained. Eight out of ten tumors were visualized on LHM images as a region with lower amplitude (5.7±1.3μm in tumors and 19.5±5.8μm in muscle). All tumors had an elongated shape running along the muscle fibers. It was possible to detect tumors larger than 4mm in width (short axis of the tumor). We performed a FUS ablation of one tumor and the ablated region was detected as well on LHM images as a reduced LHM amplitude region.

  10. Acute pancreatitis following granulosa cell tumor removal in a mare

    PubMed Central

    Gomez, Diego E.; Radtke, Catherine L.; Russell, Lauren A.; Lopez, Alfonso; Wichtel, Maureen W.

    2015-01-01

    Acute pancreatitis is a rare disease in horses and is often associated with gastrointestinal disorders. Accurate diagnosis is challenging due to the presence of nonspecific clinical signs. This case represents the first documentation of acute pancreatitis in a horse following surgery of the reproductive tract. PMID:26483579

  11. SU-E-J-07: A Functional MR Protocol for the Pancreatic Tumor Delineation

    SciTech Connect

    Andreychenko, A; Heerkens, H; Meijer, G; Vulpen, M van; Lagendijk, J; Berg, C van den

    2014-06-01

    Purpose: Pancreatic cancer is one of the cancers with the poorest survival prognosis. At the time of diagnosis most of pancreatic cancers are unresectable and those patients can be treated by radiotherapy. Radiotherapy for pancreatic cancer is limited due to uncertainties in CT-based delineations. MRI provides an excellent soft tissue contrast. Here, an MR protocol is developed to improve delineations for radiotherapy treatment of pancreatic cancer. In a later stage this protocol can also be used for on-line visualization of the pancreas during MRI guided treatments. Methods: Nine pancreatic cancer patients were included. The MR protocol included T2 weighted(T2w), T1 weighted(T1w), diffusion weighted(DWI) and dynamic contrast enhanced(DCE) techniques. The tumor was delineated on T2w and T1w MRI by an experienced radiation oncologist. Healthy pancreas or pancreatitis (assigned by the oncologist based on T2w) areas were also delineated. Apparent diffusion coefficient(ADC), and area under the curve(AUC)/time to peak(TTP) maps were obtained from DWI and DCE scans, respectively. Results: A clear demarcation of tumor area was visible on b800 DWI images in 5 patients. ADC maps of those patients characterized tumor as an area with restricted water diffusion. Tumor delineations based on solely DCE were possible in 7 patients. In 6 of those patients AUC maps demonstrated tumor heterogeneity: a hypointense area with a hyperintense ring. TTP values clearly discriminated the tumor and the healthy pancreas but could not distinguish tumor and the pancreatitis accurately. Conclusion: MR imaging results in a more pronounced tumor contrast than contrast enhanced CT. The addition of quantitative, functional MRI provides valuable, additional information to the radiation oncologist on the spatial tumor extent by discriminating tumor from the healthy pancreas(TTP, DWI) and characterizing the tumor(ADC). Our findings indicate that tumor delineation in pancreatic cancer can greatly

  12. Prognostic significance of ATM and cyclin B1 in pancreatic neuroendocrine tumor.

    PubMed

    Shin, Jae Uk; Lee, Chang Hoon; Lee, Kyu Taek; Lee, Jong Kyun; Lee, Kwang Hyuck; Kim, Kwang Min; Kim, Kyoung-Mee; Park, Sang-Mo; Rhee, Jong Chul

    2012-10-01

    Ataxia telangiectasia mutated kinase (ATM) and cyclin B1 are involved in cell cycle control. The prognostic significance of both molecules has not yet been investigated in pancreatic neuroendocrine tumors. The aim of this study was to evaluate the clinical and prognostic significance of ATM and cyclin B1 in patients with pancreatic neuroendocrine tumors. A total of 107 pancreatic neuroendocrine tumor specimens that were surgically resected were immunohistochemically investigated using the tissue microarray technique. Clinicopathologic results and survival were evaluated retrospectively. High expression of ATM and cyclin B1 was related to well-differentiated endocrine tumors of the World Health Organization (WHO) classification, but not related to TNM stages. The high ATM expression group (ATM ≥ 4) had a significantly smaller tumor size, lower recurrence rate, more number of functioning tumor, and well differentiation of WHO classification. The high cyclin B1 expression group (cyclin B1 ≥ 5) was related to smaller tumor size, less vascular invasion, less recurrence rate, and less death rate. However, cyclin B1 was the only significant factor for survival following multivariate analysis (p = 0.008; OR, 0.54; 95 % CI, 0.35-0.85). The current results suggested that expression of ATM and cyclin B1 may be useful markers to identify patients with poor prognosis who may benefit from close follow-up and aggressive therapy in pancreatic neuroendocrine tumors.

  13. Double germline mutations in APC and BRCA2 in an individual with a pancreatic tumor.

    PubMed

    Goehringer, Caroline; Sutter, Christian; Kloor, Matthias; Gebert, Johannes; Slater, Emily P; Keller, Monika; Treiber, Irmgard; Ganschow, Petra; Kadmon, Martina; Moog, Ute

    2017-04-01

    We report on three brothers affected by pancreatic tumors, all due to different causes, including mutations associated with two different cancer predisposition syndromes in the same individual. In the index patient a germline mutation both in the APC and BRCA2 gene was identified while one affected brother showed the BRCA2 mutation only and another brother is supposed to have developed pancreatic cancer due to multiple non-genetic risk factors. We outline the impact of a double germline mutation in two tumor predisposition genes in one individual and proven heterogeneity of multiple cases of pancreatic tumors in one family. With the growing implementation of next generation sequence based panel testing for multiple genes involved in tumor predisposition syndromes, relevant variants in two (or more) genes will be found more frequently. This family illustrates the importance of family studies, especially when using gene panel tests.

  14. Overexpression of CD90 (Thy-1) in pancreatic adenocarcinoma present in the tumor microenvironment.

    PubMed

    Zhu, Jianhui; Thakolwiboon, Smathorn; Liu, Xinhua; Zhang, Min; Lubman, David M

    2014-01-01

    CD90 (Thy-1) plays important roles in oncogenesis and shows potential as a candidate marker for cancer stem cells (CSCs) in various malignancies. Herein, we investigated the expression of CD90 in pancreatic adenocarcinoma (PDAC), with a comparison to normal pancreas and non-malignant pancreatic disease, by immunohistochemical (IHC) analysis of tissue microarrays containing 183 clinical tissue specimens. Statistical analysis was performed to evaluate the correlation between CD90 expression and the major clinicopathological factors after adjustment of age and gender. The IHC data showed that CD90 was significantly overexpressed in PDAC and its metastatic cancers as compared to chronic pancreatitis and benign islet tumors, while it was negative in normal pancreas and 82.7% of adjacent normal pancreas tissues. The abundant CD90 expression was predominantly present in PDAC stroma, such as fibroblasts and vascular endothelial cells, which could serve as a promising marker to distinguish pancreatic adenocarcinoma from normal pancreas and non-malignant pancreatic diseases. Double immunostaining of CD90 with CD24, a CSC marker for PDAC, showed that there was little overlap between these two markers. However, CD90+ fibroblast cells were clustered around CD24+ malignant ducts, suggesting that CD90 may be involved in the tumor-stroma interactions and promote pancreatic cancer development. Furthermore, CD90 mostly overlapped with α-smooth muscle actin (αSMA, a marker of activated pancreatic stellate cells (PSCs)) in PDAC stroma, which demonstrated that CD90+ stromal cells consist largely of activated PSCs. Double immunostaining of CD90 and a vascular endothelial cell marker CD31 demonstrated that CD90 expression on vascular endothelial cells was significantly increased in PDACs as compared to normal pancreas and non-malignant pancreatic diseases. Our findings suggest that CD90 could serve as a promising marker for pancreatic adenocarcinoma where desmoplastic stroma plays an

  15. Pancreatic tumor detection using hypericin-based fluorescence spectroscopy and cytology

    NASA Astrophysics Data System (ADS)

    Lavu, Harish; Geary, Kevin; Fetterman, Harold R.; Saxton, Romaine E.

    2005-04-01

    Hypericin is a novel, highly fluorescent photosensitizer that exhibits selective tumor cell uptake properties and is particularly resistant to photobleaching. In this study, we have characterized hypericin uptake in human pancreatic tumor cells with relation to incubation time, cell number, and drug concentration. Ex vivo hypericin based fluorescence spectroscopy was performed to detect the presence of MIA PaCa-2 pancreatic tumor cells in the peritoneal cavity of BALB/c nude mice, as well as to quantify gross tumor burden. Hypericin based cytology of peritoneal lavage samples, using both one and two photon laser confocal microscopy, demonstrated more than a two-fold increase in fluorescence emission of pancreatic tumor cells as compared to control samples. In vitro treatment of pancreatic cancer cells with hypericin based photodynamic therapy showed tumor cell cytotoxicity in a drug dose, incident laser power, and time dependent manner. For these experiments, a continuous wavelength solid-state laser source (532 nm) was operated at power levels in the range of 100-400 mW. Potential applications of hypericin in tumor diagnosis, staging, and therapy will be presented.

  16. Molecular beacon imaging of tumor marker gene expression in pancreatic cancer cells.

    PubMed

    Yang, Lily; Cao, Zehong; Lin, Yiming; Wood, William C; Staley, Charles A

    2005-05-01

    We have developed a fluorescence imaging-based approach to detect expression of tumor marker genes in pancreatic cancer cells using molecular beacons (MBs). MBs are short hairpin oligonucleotide probes that bind to specific oligonucleotide sequences and produce fluorescent signals. MBs targeting transcripts of two tumor marker genes, mutant K-ras and survivin, were synthesized and their specificity in detection of the expression of those genes in pancreatic cancer cells was examined. We found that K-ras MBs differentially bind to mutant K-ras mRNAs, resulting in strong fluorescent signals in pancreatic cancer cells with specific mutant K-ras genes but not in normal cells or cancer cells expressing either wild type or a different mutation of the K-ras gene. Additionally, MBs targeting survivin mRNA produced a bright fluorescent signal specifically in pancreatic cancer cells. We also demonstrated that MBs labeled with different fluorophores could detect survivin and mutant K-ras mRNAs simultaneously in single cancer cells. Furthermore, we showed that survivin and K-ras MBs have a high specificity in identifying cancer cells on frozen sections of pancreatic cancer tissues. In conclusion, molecular beacon-based imaging of expression of tumor marker genes has potential for the development of novel approaches for the detection of pancreatic cancer cells.

  17. [Endocrine tumors of the gastrointestinal and pancreatic systems. Multiple endocrine adenoma from another viewpoint].

    PubMed

    Klempa, I; Helmstädter, V; Feurle, G; Röttger, P

    1980-05-01

    The 24 endocrine pancreatic tumors and 14 carcinoids were examined immunohistochemically for cholecystokinin, insulin, gastrin, GIP, glucagon, sercretin, VIP, motilin, neurotensin, pancreatic polypeptide (PP), somatostatin, and ACTH. In 12 tumors of the pancreas more than one peptide-containing cell type was observed. The clinical symptoms showed hypersecretion of only one of the hormones, however. The midgut carcinoids (jejunum, appendix) represented the classical view of the carcinoid as an argentaffin cell tumor secreting 5-hydroxytryptamine. Tumors originating in the foregut (bronchus, stomach, duodenum) and hindgut carcinoids (rectum) were nonargentaffine, containing and secreting various polypeptide hormones. We conclude that light microscopic immunohistochemical methods are useful in distinguishing endocrine from nonendocrine tumors and multihormonal syndromes (MEA) in the classification of predominant hormone-secreting tumors.

  18. Hypercalcitoninemia in a sporadic asymptomatic neuroendocrine tumor of the pancreatic tail.

    PubMed

    Machens, A; Haedecke, J; Hinze, R; Thomusch, O; Schneyer, U; Dralle, H

    2000-01-01

    Asymptomatic neuroendocrine tumors of the gastroenteropancreatic tract represent a significant challenge in terms of postoperative monitoring. A case report of a calcitonin-secreting asymptomatic neuroendocrine tumor of the pancreatic tail is presented. Hypercalcitoninemia was noted in the 76-year-old Caucasian man who had a recurrent neuroendocrine tumor of the pancreatic tail. Upon pentagastrin stimulation, basal calcitonin increased only moderately from 82.3 (<10) to 100.9 and 125 pg/ml after 2 and 5 min, respectively. Surgical removal of the neuroendocrine tumor resulted in postoperative normalization of both basal and stimulated serum calcitonin levels. On immunohistochemistry, the neuroendocrine tumor was positive for calcitonin. Routine measurements of serum calcitonin might be a highly sensitive adjunct capable of identifying a subset of neuroendocrine tumors in which calcitonin monitoring may aid in the early detection of postoperative recurrence. Copyright 2000 S. Karger AG, Basel.

  19. EFFECTS OF TUMORS ON INHALED PHARMACOLOGIC DRUGS: II. PARTICLE MOTION

    EPA Science Inventory

    ABSTRACT

    Computer simulations were conducted to describe drug particle motion in human lung bifurcations with tumors. The computations used FIDAP with a Cray T90 supercomputer. The objective was to better understand particle behavior as affected by particle characteristics...

  20. EFFECTS OF TUMORS ON INHALED PHARMACOLOGIC DRUGS: II. PARTICLE MOTION

    EPA Science Inventory

    ABSTRACT

    Computer simulations were conducted to describe drug particle motion in human lung bifurcations with tumors. The computations used FIDAP with a Cray T90 supercomputer. The objective was to better understand particle behavior as affected by particle characteristics...

  1. Carcinoma of the pancreatic head and periampullary region. Tumor staging with laparoscopy and laparoscopic ultrasonography.

    PubMed Central

    John, T G; Greig, J D; Carter, D C; Garden, O J

    1995-01-01

    OBJECTIVE: The authors performed a prospective evaluation of staging laparoscopy with laparoscopic ultrasonography in predicting surgical resectability in patients with carcinomas of the pancreatic head and periampullary region. SUMMARY BACKGROUND DATA: Pancreatic resection with curative intent is possible in a select minority of patients who have carcinomas of the pancreatic head and periampullary region. Patient selection is important to plan appropriate therapy and avoid unnecessary laparotomy in patients with unresectable disease. Laparoscopic ultrasonography is a novel technique that combines the proven benefits of staging laparoscopy with high resolution intraoperative ultrasound of the liver and pancreas, but which has yet to be evaluated critically in the staging of pancreatic malignancy. METHODS: A cohort of 40 consecutive patients referred to a tertiary referral center and with a diagnosis of potentially resectable pancreatic or periampullary cancer underwent staging laparoscopy with laparoscopic ultrasonography. The diagnostic accuracy of staging laparoscopy alone and in conjunction with laparoscopic ultrasonography was evaluated in predicting tumor resectability (absence of peritoneal or liver metastases; absence of malignant regional lymphadenopathy; tumor confined to pancreatic head or periampullary region). RESULTS: "Occult" metastatic lesions were demonstrated by staging laparoscopy in 14 patients (35%). Laparoscopic ultrasonography demonstrated factors confirming unresectable tumor in 23 patients (59%), provided staging information in addition to that of laparoscopy alone in 20 patients (53%), and changed the decision regarding tumor resectability in 10 patients (25%). Staging laparoscopy with laparoscopic ultrasonography was more specific and accurate in predicting tumor resectability than laparoscopy alone (88% and 89% versus 50% and 65%, respectively). CONCLUSIONS: Staging laparoscopy is indispensable in the detection of "occult" intra

  2. Increased Serotonin Signaling Contributes to the Warburg Effect in Pancreatic Tumor Cells Under Metabolic Stress and Promotes Growth of Pancreatic Tumors in Mice.

    PubMed

    Jiang, Shu-Heng; Li, Jun; Dong, Fang-Yuan; Yang, Jian-Yu; Liu, De-Jun; Yang, Xiao-Mei; Wang, Ya-Hui; Yang, Min-Wei; Fu, Xue-Liang; Zhang, Xiao-Xin; Li, Qing; Pang, Xiu-Feng; Huo, Yan-Miao; Li, Jiao; Zhang, Jun-Feng; Lee, Ho-Young; Lee, Su-Jae; Qin, Wen-Xin; Gu, Jian-Ren; Sun, Yong-Wei; Zhang, Zhi-Gang

    2017-07-01

    Desmoplasia and poor vascularity cause severe metabolic stress in pancreatic ductal adenocarcinomas (PDACs). Serotonin (5-HT) is a neuromodulator with neurotransmitter and neuroendocrine functions that contributes to tumorigenesis. We investigated the role of 5-HT signaling in the growth of pancreatic tumors. We measured the levels of proteins that regulate 5-HT synthesis, packaging, and degradation in pancreata from Kras(G12D/+)/Trp53(R172H/+)/Pdx1-Cre (KPC) mice, which develop pancreatic tumors, as well as in PDAC cell lines and a tissue microarray containing 81 human PDAC samples. We also analyzed expression levels of proteins involved in 5-HT synthesis and degradation by immunohistochemical analysis of a tissue microarray containing 311 PDAC specimens, and associated expression levels with patient survival times. 5-HT level in 14 matched PDAC tumor and non-tumor tissues were analyzed by ELISA. PDAC cell lines were incubated with 5-HT and cell survival and apoptosis were measured. We analyzed expression of the 5-HT receptor HTR2B in PDAC cells and effects of receptor agonists and antagonists, as well as HTR2B knockdown with small hairpin RNAs. We determined the effects of 5-HT stimulation on gene expression profiles of BxPC-3 cells. Regulation of glycolysis by 5-HT signaling via HTR2B was assessed by immunofluorescence and immunoprecipitation analyses, as well as by determination of the extracellular acid ratio, glucose consumption, and lactate production. Primary PDACs, with or without exposure to SB204741 (a selective antagonist of HTR2B), were grown as xenograft tumors in mice, and SB204741 was administered to tumor-bearing KPC mice; tumor growth and metabolism were measured by imaging analyses. In immunohistochemical analysis of a tissue microarray of PDAC specimens, increased levels of TPH1 and decreased level of MAOA, which regulate 5-HT synthesis and degradation, correlated with stage and size of PDACs and shorter patient survival time. We found levels

  3. Mitigation of motion artifacts in CBCT of lung tumors based on tracked tumor motion during CBCT acquisition.

    PubMed

    Lewis, John H; Li, Ruijiang; Jia, Xun; Watkins, W Tyler; Lou, Yifei; Song, William Y; Jiang, Steve B

    2011-09-07

    An algorithm capable of mitigating respiratory motion blurring artifacts in cone-beam computed tomography (CBCT) lung tumor images based on the motion of the tumor during the CBCT scan is developed. The tumor motion trajectory and probability density function (PDF) are reconstructed from the acquired CBCT projection images using a recently developed algorithm Lewis et al (2010 Phys. Med. Biol. 55 2505-22). Assuming that the effects of motion blurring can be represented by convolution of the static lung (or tumor) anatomy with the motion PDF, a cost function is defined, consisting of a data fidelity term and a total variation regularization term. Deconvolution is performed through iterative minimization of this cost function. The algorithm was tested on digital respiratory phantom, physical respiratory phantom and patient data. A clear qualitative improvement is evident in the deblurred images as compared to the motion-blurred images for all cases. Line profiles show that the tumor boundaries are more accurately and clearly represented in the deblurred images. The normalized root-mean-squared error between the images used as ground truth and the motion-blurred images are 0.29, 0.12 and 0.30 in the digital phantom, physical phantom and patient data, respectively. Deblurring reduces the corresponding values to 0.13, 0.07 and 0.19. Application of a -700 HU threshold to the digital phantom results in tumor dimension measurements along the superior-inferior axis of 2.8, 1.8 and 1.9 cm in the motion-blurred, ground truth and deblurred images, respectively. Corresponding values for the physical phantom are 3.4, 2.7 and 2.7 cm. A threshold of -500 HU applied to the patient case gives measurements of 3.1, 1.6 and 1.7 cm along the SI axis in the CBCT, 4DCT and deblurred images, respectively. This technique could provide more accurate information about a lung tumor's size and shape on the day of treatment.

  4. Amenorrhea as a rare drug-related adverse event associated with everolimus for pancreatic neuroendocrine tumors.

    PubMed

    Kawaguchi, Yoshiaki; Maruno, Atsuko; Kawashima, Yohei; Ito, Hiroyuki; Ogawa, Masami; Mine, Tetsuya

    2014-11-14

    The patient was an asymptomatic 43-year-old woman. Abdominal ultrasonography and enhanced computed tomography showed a tumor lesion accompanied by multiple cystic changes in the liver and the pancreatic tail. Endoscopic ultrasound-fine needle aspiration was performed on the pancreatic tumor lesion and revealed pancreatic neuroendocrine tumor (PNET). As it was unresectable due to multiple liver metastases, the decision was made to initiate treatment with everolimus and transcatheter arterial chemoembolization. The patient ceased menstruating after the start of everolimus administration. When the administration was discontinued due to interstitial lung disease, menstruation resumed, but then again stopped with everolimus resumption. An association between everolimus and amenorrhea was highly suspected. Amenorrhea occurred as a rare adverse event of everolimus. As the younger women might be included in PNETs patients, we should put this adverse event into consideration.

  5. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

    NASA Astrophysics Data System (ADS)

    Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya'an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

    2014-12-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  6. Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

    PubMed Central

    Koay, Eugene J.; Baio, Flavio E.; Ondari, Alexander; Truty, Mark J.; Cristini, Vittorio; Thomas, Ryan M.; Chen, Rong; Chatterjee, Deyali; Kang, Ya’an; Zhang, Joy; Court, Laurence; Bhosale, Priya R.; Tamm, Eric P.; Qayyum, Aliya; Crane, Christopher H.; Javle, Milind; Katz, Matthew H.; Gottumukkala, Vijaya N.; Rozner, Marc A.; Shen, Haifa; Lee, Jeffrey E.; Wang, Huamin; Chen, Yuling; Plunkett, William; Abbruzzese, James L.; Wolff, Robert A.; Maitra, Anirban; Ferrari, Mauro; Varadhachary, Gauri R.; Fleming, Jason B.

    2014-01-01

    There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of

  7. Maintaining tumor targeting accuracy in real-time motion compensation systems for respiration-induced tumor motion.

    PubMed

    Malinowski, Kathleen; McAvoy, Thomas J; George, Rohini; Dieterich, Sonja; D'Souza, Warren D

    2013-07-01

    To determine how best to time respiratory surrogate-based tumor motion model updates by comparing a novel technique based on external measurements alone to three direct measurement methods. Concurrently measured tumor and respiratory surrogate positions from 166 treatment fractions for lung or pancreas lesions were analyzed. Partial-least-squares regression models of tumor position from marker motion were created from the first six measurements in each dataset. Successive tumor localizations were obtained at a rate of once per minute on average. Model updates were timed according to four methods: never, respiratory surrogate-based (when metrics based on respiratory surrogate measurements exceeded confidence limits), error-based (when localization error ≥ 3 mm), and always (approximately once per minute). Radial tumor displacement prediction errors (mean ± standard deviation) for the four schema described above were 2.4 ± 1.2, 1.9 ± 0.9, 1.9 ± 0.8, and 1.7 ± 0.8 mm, respectively. The never-update error was significantly larger than errors of the other methods. Mean update counts over 20 min were 0, 4, 9, and 24, respectively. The same improvement in tumor localization accuracy could be achieved through any of the three update methods, but significantly fewer updates were required when the respiratory surrogate method was utilized. This study establishes the feasibility of timing image acquisitions for updating respiratory surrogate models without direct tumor localization.

  8. Maintaining tumor targeting accuracy in real-time motion compensation systems for respiration-induced tumor motion

    PubMed Central

    Malinowski, Kathleen; McAvoy, Thomas J.; George, Rohini; Dieterich, Sonja; D’Souza, Warren D.

    2013-01-01

    Purpose: To determine how best to time respiratory surrogate-based tumor motion model updates by comparing a novel technique based on external measurements alone to three direct measurement methods. Methods: Concurrently measured tumor and respiratory surrogate positions from 166 treatment fractions for lung or pancreas lesions were analyzed. Partial-least-squares regression models of tumor position from marker motion were created from the first six measurements in each dataset. Successive tumor localizations were obtained at a rate of once per minute on average. Model updates were timed according to four methods: never, respiratory surrogate-based (when metrics based on respiratory surrogate measurements exceeded confidence limits), error-based (when localization error ≥3 mm), and always (approximately once per minute). Results: Radial tumor displacement prediction errors (mean ± standard deviation) for the four schema described above were 2.4 ± 1.2, 1.9 ± 0.9, 1.9 ± 0.8, and 1.7 ± 0.8 mm, respectively. The never-update error was significantly larger than errors of the other methods. Mean update counts over 20 min were 0, 4, 9, and 24, respectively. Conclusions: The same improvement in tumor localization accuracy could be achieved through any of the three update methods, but significantly fewer updates were required when the respiratory surrogate method was utilized. This study establishes the feasibility of timing image acquisitions for updating respiratory surrogate models without direct tumor localization. PMID:23822413

  9. TLR7 and TLR8 expression increases tumor cell proliferation and promotes chemoresistance in human pancreatic cancer

    PubMed Central

    GRIMMIG, TANJA; MATTHES, NIELS; HOELAND, KATHARINA; TRIPATHI, SUDIPTA; CHANDRAKER, ANIL; GRIMM, MARTIN; MOENCH, ROMANA; MOLL, EVA-MARIA; FRIESS, HELMUT; TSAUR, IGOR; BLAHETA, ROMAN A.; GERMER, CRISTOPH T.; WAAGA-GASSER, ANA MARIA; GASSER, MARTIN

    2015-01-01

    Chronic inflammation as an important epigenetic and environmental factor for putative tumorigenesis and tumor progression may be associated with specific activation of Toll-like receptors (TLR). Recently, carcinogenesis has been suggested to be dependent on TLR7 signaling. In the present study, we determined the role of both TLR7 and TLR8 expression and signaling in tumor cell proliferation and chemoresistance in pancreatic cancer. Expression of TLR7/TLR8 in UICC stage I–IV pancreatic cancer, chronic pancreatitis, normal pancreatic tissue and human pancreatic (PANC1) cancer cell line was examined. For in vitro/in vivo studies TLR7/TLR8 overexpressing PANC1 cell lines were generated and analyzed for effects of (un-)stimulated TLR expression on tumor cell proliferation and chemoresistance. TLR expression was increased in pancreatic cancer, with stage-dependent upregulation in advanced tumors, compared to earlier stages and chronic pancreatitis. Stimulation of TLR7/TLR8 overexpressing PANC1 cells resulted in elevated NF-κB and COX-2 expression, increased cancer cell proliferation and reduced chemosensitivity. More importantly, TLR7/TLR8 expression increased tumor growth in vivo. Our data demonstrate a stage-dependent upregulation of both TLR7 and TLR8 expression in pancreatic cancer. Functional analysis in human pancreatic cancer cells point to a significant role of both TLRs in chronic inflammation-mediated TLR7/TLR8 signaling leading to tumor cell proliferation and chemoresistance. PMID:26134824

  10. Targeting inhibitors of the tumor suppressor PP2A for the treatment of pancreatic cancer.

    PubMed

    Farrell, Amy S; Allen-Petersen, Brittany; Daniel, Colin J; Wang, Xiaoyan; Wang, Zhiping; Rodriguez, Sarah; Impey, Soren; Oddo, Jessica; Vitek, Michael P; Lopez, Charles; Christensen, Dale J; Sheppard, Brett; Sears, Rosalie C

    2014-06-01

    Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways that have shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor protein phosphatase 2A (PP2A). Here, the endogenous inhibitors of PP2A, SET (also known as I2PP2A) and cancerous inhibitor of PP2A (CIP2A), were shown to be overexpressed in human pancreatic cancer, contributing to decreased PP2A activity and overexpression and stabilization of the oncoprotein c-Myc, a key PP2A target. Knockdown of SET or CIP2A increases PP2A activity, increases c-Myc degradation, and decreases the tumorigenic potential of pancreatic cancer cell lines both in vitro and in vivo. Moreover, treatment with a novel SET inhibitor, OP449, pharmacologically recapitulates the phenotypes and significantly reduces proliferation and tumorigenic potential of several pancreatic cancer cell lines, with an accompanying attenuation of cell growth and survival signaling. Furthermore, primary cells from patients with pancreatic cancer were sensitive to OP449 treatment, indicating that PP2A-regulated pathways are highly relevant to this deadly disease. The PP2A inhibitors SET and CIP2A are overexpressed in human pancreatic cancer and are important for pancreatic cancer cell growth and transformation; thus, antagonizing SET and/or CIP2A may be an innovative approach for the treatment of human pancreatic cancer. ©2014 American Association for Cancer Research.

  11. Resection of postoperative liver metastasis from pancreatic neuroendocrine tumors: report of one case

    PubMed Central

    Chen, Xiao; Ren, Hu; Chi, Yihebali; He, Shun; Huang, Zhen; Hu, Xuhui

    2016-01-01

    Pancreatic neuroendocrine tumor (pNET) is a rare type of pancreatic tumors. The incidence of pNET shows a gradually increasing trend in recent years. Except insulinoma, majority of pNET are metastatic when diagnosis. And liver is the most common organ of distant metastases. Liver metastases are the main determinant for long-term survival and quality of life of patients with pNET. A case of liver metastases of pNET of a 44-year-old female patient is presented in this study. Then we have a brief discussion of the diagnosis and multidisciplinary treatment of advanced pNET. PMID:28138614

  12. Positional Reproducibility of Pancreatic Tumors Under End-Exhalation Breath-Hold Conditions Using a Visual Feedback Technique

    SciTech Connect

    Nakamura, Mitsuhiro; Shibuya, Keiko; Shiinoki, Takehiro; Matsuo, Yukinori; Nakamura, Akira; Nakata, Manabu; Sawada, Akira; Mizowaki, Takashi; Hiraoka, Masahiro

    2011-04-01

    Purpose: To assess positional reproducibility of pancreatic tumors under end-exhalation (EE) breath-hold (BH) conditions with a visual feedback technique based on computed tomography (CT) images. Methods and Materials: Ten patients with pancreatic cancer were enrolled in an institutional review board-approved trial. All patients were placed in a supine position on an individualized vacuum pillow with both arms raised. At the time of CT scan, they held their breath at EE with the aid of video goggles displaying their abdominal displacement. Each three-consecutive helical CT data set was acquired four times (sessions 1-4; session 1 corresponded to the time of CT simulation). The point of interest within or in proximity to a gross tumor volume was defined based on certain structural features. The positional variations in point of interest and margin size required to cover positional variations were assessed. Results: The means {+-} standard deviations (SDs) of intrafraction positional variations were 0.0 {+-} 1.1, 0.1 {+-} 1.2, and 0.1 {+-} 1.0 mm in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively (p = 0.726). The means {+-} SDs of interfraction positional variations were 0.3 {+-} 2.0, 0.8 {+-} 1.8, and 0.3 {+-} 1.8 mm in the LR, AP, and SI directions, respectively (p = 0.533). Population-based margin sizes required to cover 95th percentiles of the overall positional variations were 4.7, 5.3, and 4.9 mm in the LR, AP, and SI directions, respectively. Conclusions: A margin size of 5 mm was needed to cover the 95th percentiles of the overall positional variations under EE-BH conditions, using this noninvasive approach to motion management for pancreatic tumors.

  13. Targeting Inhibitors of the Tumor Suppressor PP2A for the Treatment of Pancreatic Cancer

    PubMed Central

    Farrell, Amy S.; Allen-Petersen, Brittany; Daniel, Colin J.; Wang, Xiaoyan; Wang, Zhiping; Rodriguez, Sarah; Impey, Soren; Oddo, Jessica; Vitek, Michael P.; Lopez, Charles; Christensen, Dale J.; Sheppard, Brett; Sears, Rosalie C.

    2014-01-01

    Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor, protein phosphatase 2A (PP2A). Here, the endogenous inhibitors of PP2A, SET (also known as I2PP2A) and Cancerous Inhibitor of PP2A (CIP2A), were shown to be overexpressed in human pancreatic cancer, contributing to decreased PP2A activity, and overexpression and stabilization of the oncoprotein c-Myc, a key PP2A target. Knockdown of SET or CIP2A increases PP2A activity, increases c-Myc degradation, and decreases the tumorigenic potential of pancreatic cancer cell lines both in vitro and in vivo. Moreover, treatment with a novel SET inhibitor, OP449, pharmacologically recapitulates the phenotypes and significantly reduces proliferation and tumorigenic potential of several pancreatic cancer cell lines, with an accompanying attenuation of cell growth and survival signaling. Furthermore, primary cells from pancreatic cancer patients were sensitive to OP449 treatment, indicating that PP2A regulated pathways are highly relevant to this deadly disease. PMID:24667985

  14. B-mode and contrast-enhancement characteristics of small nonincidental neuroendocrine pancreatic tumors

    PubMed Central

    Braden, Barbara; Jenssen, Christian; D’Onofrio, Mirko; Hocke, Michael; Will, Uwe; Möller, Kathleen; Ignee, Andre; Dong, Yi; Cui, Xin-Wu; Săftoiu, Adrian; Dietrich, Christoph F.

    2017-01-01

    Background and Objectives: Imaging of the pancreas for detection of neuroendocrine tumors is indicated as surveillance in multiple endocrine neoplasia type 1 (MEN1) or if typical clinical symptoms combined with hormone production raise the suspicion of a neuroendocrine tumor. Endoscopic ultrasound (EUS) is considered the best imaging modality to detect small pancreatic tumors. However, little is known about how small pancreatic neuroendocrine tumors (pNETs) present on EUS. Patients and Methods: In this multicenter study, we retrospectively analyzed the endosonographic characteristics of small pNETs which had been detected due to typical biochemistry and clinical symptoms or during surveillance of MEN 1. Only small pancreatic tumors ≤15 mm with histological confirmation as pNET were included. B-mode and contrast-enhanced ultrasound- and EUS patterns were analyzed. Results: Among 32 patients with histologically proven small pNETs, 7 patients had known MEN1. Among the pNETs, 20 were insulinoma, 2 gastrinoma, 3 glucagonoma, 6 nonfunctional in MEN1, and one PPoma. 94% of the pNET appeared hypoechogenic, only 1 isoechogenic and 1 hyperechogenic. After contrast injection, 90% of the pNETS showed hyperenhancement compared to the surrounding pancreatic parenchyma. Conclusion: The high spatial resolution of EUS allows detection and even cytological confirmation of pNET <7 mm diameter. Hypoechogenicity in B-mode and hyperenhancement after injection of contrast agents are endosonographic characteristics of small pNET and present in >90% of pNETs. PMID:28218201

  15. Intraductal delivery of adenoviruses targets pancreatic tumors in transgenic Ela-myc mice and orthotopic xenografts.

    PubMed

    José, Anabel; Sobrevals, Luciano; Miguel Camacho-Sánchez, Juan; Huch, Meritxell; Andreu, Núria; Ayuso, Eduard; Navarro, Pilar; Alemany, Ramon; Fillat, Cristina

    2013-01-01

    Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route. We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTKT plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TKT oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p less than 0.0001) when combined with GCV. Of notice, both AduPARTKT and ICOVIR15-TKT antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration. In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors.

  16. Intraductal Delivery of Adenoviruses Targets Pancreatic Tumors in Transgenic Ela-myc Mice and Orthotopic Xenografts

    PubMed Central

    José, Anabel; Sobrevals, Luciano; Camacho-Sánchez, Juan Miguel; Huch, Meritxell; Andreu, Núria; Ayuso, Eduard; Navarro, Pilar; Alemany, Ramon; Fillat, Cristina

    2013-01-01

    Gene-based anticancer therapies delivered by adenoviruses are limited by the poor viral distribution into the tumor. In the current work we have explored the feasibility of targeting pancreatic tumors through a loco-regional route. We have taken advantage of the ductal network in the pancreas to retrogradelly inject adenoviruses through the common bile duct in two different mouse models of pancreatic carcinogenesis: The transgenic Ela-myc mice that develop mixed neoplasms displaying both acinar-like and duct-like neoplastic cells affecting the whole pancreas; and mice bearing PANC-1 and BxPC-3 orthotopic xenografts that constitute a model of localized human neoplastic tumors. We studied tumor targeting and the anticancer effects of newly thymidine kinase-engineered adenoviruses both in vitro and in vivo, and conducted comparative studies between intraductal or intravenous administration. Our data indicate that the intraductal delivery of adenovirus efficiently targets pancreatic tumors in the two mouse models. The in vivo application of AduPARTKT plus ganciclovir (GCV) treatment induced tumor regression in Ela-myc mice. Moreover, the intraductal injection of ICOVIR15-TKT oncolytic adenoviruses significantly improved mean survival of mice bearing PANC-1 and BxPC-3 pancreatic xenografts from 30 to 52 days and from 20 to 68 days respectively (p<0.0001) when combined with GCV. Of notice, both AduPARTKT and ICOVIR15-TKT antitumoral responses were stronger by ductal viral application than intravenously, in line with the 38-fold increase in pancreas transduction observed upon ductal administration. In summary our data show that cytotoxic adenoviruses retrogradelly injected to the pancreas can be a feasible approach to treat localized pancreatic tumors. PMID:23328228

  17. Circulating tumor DNA as a liquid biopsy target for detection of pancreatic cancer.

    PubMed

    Takai, Erina; Yachida, Shinichi

    2016-10-14

    Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic options for advanced disease. Therefore, there is a need for minimally-invasive diagnostic tools for detecting pancreatic cancer at an early stage, when curative surgery and also novel therapeutic approaches including precision medicine may be feasible. The "liquid biopsy" addresses these unmet clinical needs based on the concept that simple peripheral blood sampling and detection of circulating tumor DNA (ctDNA) could provide diagnostic information. In this review, we provide an overview of the current status of blood-based tests for diagnosis of pancreatic cancer and the potential utility of ctDNA for precision medicine. We also discuss challenges that remain to be addressed in developing practical ctDNA-based liquid biopsy approaches for early diagnosis of pancreatic cancer.

  18. Circulating tumor DNA as a liquid biopsy target for detection of pancreatic cancer

    PubMed Central

    Takai, Erina; Yachida, Shinichi

    2016-01-01

    Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic options for advanced disease. Therefore, there is a need for minimally-invasive diagnostic tools for detecting pancreatic cancer at an early stage, when curative surgery and also novel therapeutic approaches including precision medicine may be feasible. The “liquid biopsy” addresses these unmet clinical needs based on the concept that simple peripheral blood sampling and detection of circulating tumor DNA (ctDNA) could provide diagnostic information. In this review, we provide an overview of the current status of blood-based tests for diagnosis of pancreatic cancer and the potential utility of ctDNA for precision medicine. We also discuss challenges that remain to be addressed in developing practical ctDNA-based liquid biopsy approaches for early diagnosis of pancreatic cancer. PMID:27784960

  19. Harmonic Motion Imaging (HMI) for Tumor Imaging and Treatment Monitoring.

    PubMed

    Konofagou, Elisa E; Maleke, Caroline; Vappou, Jonathan

    2012-01-01

    Palpation is an established screening procedure for the detection of several superficial cancers including breast, thyroid, prostate, and liver tumors through both self and clinical examinations. This is because solid masses typically have distinct stiffnesses compared to the surrounding normal tissue. In this paper, the application of Harmonic Motion Imaging (HMI) for tumor detection based on its stiffness as well as its relevance in thermal treatment is reviewed. HMI uses a focused ultrasound (FUS) beam to generate an oscillatory acoustic radiation force for an internal, non-contact palpation to internally estimate relative tissue hardness. HMI studies have dealt with the measurement of the tissue dynamic motion in response to an oscillatory acoustic force at the same frequency, and have been shown feasible in simulations, phantoms, ex vivo human and bovine tissues as well as animals in vivo. Using an FUS beam, HMI can also be used in an ideal integration setting with thermal ablation using high-intensity focused ultrasound (HIFU), which also leads to an alteration in the tumor stiffness. In this paper, a short review of HMI is provided that encompasses the findings in all the aforementioned areas. The findings presented herein demonstrate that the HMI displacement can accurately depict the underlying tissue stiffness, and the HMI image of the relative stiffness could accurately detect and characterize the tumor or thermal lesion based on its distinct properties. HMI may thus constitute a non-ionizing, cost-efficient and reliable complementary method for noninvasive tumor detection, localization, diagnosis and treatment monitoring.

  20. Growth hormone-releasing hormone (GRH)-producing pancreatic tumor with no evidence of multiple endocrine neoplasia type 1.

    PubMed

    Kawa, S; Ueno, T; Iijima, A; Midorikawa, T; Fujimori, Y; Tokoo, M; Oguchi, H; Kiyosawa, K; Imai, Y; Kaneko, G; Kuroda, T; Hashizume, K; Osamura, R Y; Katakami, H

    1997-07-01

    The characteristic features of a 48-year-old male presenting with isolated acromegaly caused by a GRH-producing pancreatic endocrine tumor bearing no relation to MEN1 was reported. The clinical features, laboratory findings, and sellar enlargement were improved after removal of the pancreatic tumor. The resected pancreatic tumor showed positive GRH immunoreactivity and contained abundant GRH mRNA. This tumor is extremely rare and to date only 10 cases have been reported. In the management of acromegaly, the measurement of GRH is recommended and the search for an ectopic source will prevent unnecessary and potentially ineffective pituitary surgery.

  1. A tumor vessel-targeting fusion protein elicits a chemotherapeutic bystander effect in pancreatic ductal adenocarcinoma

    PubMed Central

    Chen, Chun-Te; Chen, Yi-Chun; Du, Yi; Han, Zhenbo; Ying, Haoqiang; Bouchard, Richard R; Hsu, Jennifer L; Hsu, Jung-Mao; Mitcham, Trevor M; Chen, Mei-Kuang; Sun, Hui-Lung; Chang, Shih-Shin; Li, Donghui; Chang, Ping; DePinho, Ronald A; Hung, Mien-Chie

    2017-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by a prominent desmoplastic stroma that may constrain tumor progression but also limit the access of therapeutic drugs. In this study, we explored a tumor-targeting strategy that enlists an engineered anti-angiogenic protein consisting of endostatin and cytosine deaminase linked to uracil phosphoribosyltransferase (EndoCD). This protein selectively binds to tumor vessels to compromise tumor angiogenesis and converts the non-toxic 5-fluorocytosine (5-FC) to the cytotoxic 5-fluorouracil to produce a chemotherapeutic bystander effect at the pancreatic tumor site. We found that resveratrol increased the protein stability of EndoCD through suppression of chymotrypsin-like proteinase activity and synergistically enhances EndoCD-mediated 5-FC-induced cell killing. In various PDAC mouse models, the EndoCD/5-FC/resveratrol regimen decreased intratumoral vascular density and stroma formation and enhances apoptosis in tumors cells as well as in surrounding endothelial, pancreatic stellate, and immune cells, leading to reduced tumor growth and extended survival. Thus, the EndoCD/5-FC/resveratrol combination may be an effective treatment option for PDAC. PMID:28401019

  2. Agenesis of the dorsal pancreas and its association with pancreatic tumors.

    PubMed

    Sakpal, Sujit Vijay; Sexcius, Lucretia; Babel, Nitin; Chamberlain, Ronald Scott

    2009-05-01

    Morphogenesis of the pancreas is a complex process; nevertheless, congenital anomalies are rare. At embryogenesis, the pancreas develops from the endoderm-lined dorsal and ventral buds of the duodenum. The ventral bud gives rise to the lower head and uncinate process of the pancreas; whereas, the dorsal bud gives rise to the upper head, isthmus, body, and tail of the pancreas. Rarely, developmental failure of the dorsal pancreatic bud at embryogenesis results in the agenesis of the dorsal pancreas--neck, body, and tail. Even rarer is the association of pancreatic tumors with agenesis of the dorsal pancreas. In addition to citing our case, we provide a comprehensive review on agenesis of the dorsal pancreas and its association with pancreatic tumors.

  3. Harmonic Motion Microwave Doppler Imaging method for breast tumor detection.

    PubMed

    Top, Can Barıs; Tafreshi, Azadeh Kamali; Gençer, Nevzat G

    2014-01-01

    Harmonic Motion Microwave Doppler Imaging (HMMDI) method is recently proposed as a non-invasive hybrid breast imaging technique for tumor detection. The acquired data depend on acoustic, elastic and electromagnetic properties of the tissue. The potential of the method is analyzed with simulation studies and phantom experiments. In this paper, the results of these studies are summarized. It is shown that HMMDI method has a potential to detect malignancies inside fibro-glandular tissue.

  4. Overcoming the stromal barrier for targeted delivery of HPMA copolymers to pancreatic tumors.

    PubMed

    Buckway, Brandon; Wang, Yongjian; Ray, Abhijit; Ghandehari, Hamidreza

    2013-11-01

    Delivery of macromolecules to pancreatic cancer is inhibited by a dense extracellular matrix composed of hyaluronic acid, smooth muscle actin and collagen fibers. Hyaluronic acid causes a high intratumoral fluidic pressure which prevents diffusion and penetration into the pancreatic tumor. This study involves the breaking down of hyaluronic acid by treating CAPAN-1 xenograft tumors in athymic nu/nu mice with targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers radiolabeled with (111)In for single photon emission computerized tomography (SPECT) imaging. Two targeting strategies were investigated including αvβ3 integrin and HER2 receptors. HPMA copolymers were targeted to these receptors by conjugating short peptide ligands cRGDfK and KCCYSL to the side chains of the copolymer. Results demonstrate that tumor targeting can be achieved in vivo after treatment with hyaluronidase. This approach shows promise for enhanced delivery of polymer-peptide conjugates to solid tumors.

  5. Pharmacokinetically Guided Everolimus in Patients With Breast Cancer, Pancreatic Neuroendocrine Tumors, or Kidney Cancer

    ClinicalTrials.gov

    2016-12-09

    Estrogen Receptor-positive Breast Cancer; Gastrinoma; Glucagonoma; HER2-negative Breast Cancer; Insulinoma; Mucositis; Oral Complications; Pancreatic Polypeptide Tumor; Progesterone Receptor-positive Breast Cancer; Recurrent Breast Cancer; Recurrent Islet Cell Carcinoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Renal Cell Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Renal Cell Cancer

  6. Circulating Tumor Cells in the Diagnosis and Management of Pancreatic Cancer

    PubMed Central

    Cen, Putao; Ni, Xiaoling; Yang, Jingxuan; Graham, David Y.; Li, Min

    2012-01-01

    Pancreatic cancers are typically resistant to chemo and radiation therapy and are predisposed to distant metastases. Circulating tumor cells (CTCs) are tumor cells disseminated from primary and metastatic sites and can be isolated from peripheral blood. CTC may overcome the limitation of the current available tumor markers, CA19-9. As a surrogate for ‘real-time biopsy’, CTCs allow recurrent assessment of a tumor’s biological activity. We review the current methodologies for CTCs extraction and characterization including antibody-based immunological assays, PCR-based assays, and novel technologies based on the physical or biological characteristics of CTCs. CTCs also provide an accessible link to the existence of epithelial to mesenchymal transition, tumor stem cell markers, and ongoing clonal mutations and epigenetic changes in the tumor. We also explore the potential of using CTC profiling in diagnosis, selection of neoadjuvant and adjuvant therapy, detection of recurrent disease, examination of pharmacodynamic biomarkers, as well as in gene therapy and immunotherapy for pancreatic cancer. Ongoing CTC characterization not only has the potential to represent all cells shed from primary pancreatic tumor and each metastatic site, but also allows dynamic sampling at multiple time points during the clinical course to identify the subpopulations of CTCs and the specific molecules driving metastasis and chemo resistance. We predict that CTC genotyping and phenotyping will play an increasing role in personalized therapy and in identification of novel therapeutic targets as well as monitoring the course and status of the disease. PMID:22683404

  7. Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor-stromal cross-talk.

    PubMed

    Averett, Courey; Bhardwaj, Arun; Arora, Sumit; Srivastava, Sanjeev K; Khan, Mohammad Aslam; Ahmad, Aamir; Singh, Seema; Carter, James E; Khushman, Moh'd; Singh, Ajay P

    2016-11-01

    The poor clinical outcome of pancreatic cancer (PC) is largely attributed to its aggressive nature and refractoriness to currently available therapeutic modalities. We previously reported antitumor efficacy of honokiol (HNK), a phytochemical isolated from various parts of Magnolia plant, against PC cells in short-term in vitro growth assays. Here, we report that HNK reduces plating efficiency and anchorage-independent growth of PC cells and suppresses their migration and invasiveness. Furthermore, significant inhibition of pancreatic tumor growth by HNK is observed in orthotopic mouse model along with complete-blockage of distant metastases. Histological examination suggests reduced desmoplasia in tumors from HNK-treated mice, later confirmed by immunohistochemical analyses of myofibroblast and extracellular matrix marker proteins (α-SMA and collagen I, respectively). At the molecular level, HNK treatment leads to decreased expression of sonic hedgehog (SHH) and CXCR4, two established mediators of bidirectional tumor-stromal cross-talk, both in vitro and in vivo . We also show that the conditioned media (CM) from HNK-treated PC cells have little growth-inducing effect on pancreatic stellate cells (PSCs) that could be regained by the addition of exogenous recombinant SHH. Moreover, pretreatment of CM of vehicle-treated PC cells with SHH-neutralizing antibody abolishes their growth-inducing potential on PSCs. Likewise, HNK-treated PC cells respond poorly to CM from PSCs due to decreased CXCR4 expression. Lastly, we show that the transfection of PC cells with constitutively active IKKβ mutant reverses the suppressive effect of HNK on nuclear factor-kappaB activation and partially restores CXCR4 and SHH expression. Taken together, these findings suggest that HNK interferes with tumor-stromal cross-talk via downregulation of CXCR4 and SHH and decreases pancreatic tumor growth and metastasis. © The Author 2016. Published by Oxford University Press. All rights reserved

  8. Calcitonin-secreting pancreatic neuroendocrine tumors: a case report and review of the literature.

    PubMed

    Kováčová, Martina; Filková, Marta; Potočárová, Mária; Kiňová, Soňa; Pajvani, Utpal B

    2014-08-01

    We report the presentation and novel therapy of a calcitonin-secreting pancreatic neuroendocrine tumor (PNET) and review the literature on this unusual neoplasm. We cite the history of a 38-year-old male who presented with fatigue, weight loss, and diarrhea and was found to have a pancreatic head mass on cross-sectional imaging, as well as liver metastases. The patient's laboratory evaluation was notable for a >100-fold elevation of the peptide hormone calcitonin in serum. As calcitonin is typically secreted by thyroid C-cells, hypercalcitoninemia is considered a marker for medullary thyroid cancer (MTC) or C-cell hyperplasia, but it may be present in several physiologic or pathologic conditions or may be ectopically secreted in rare PNETs. An octreotide scan confirmed the presence of somatostatin (SST) receptors on the pancreatic mass and liver metastases, leading to the diagnosis of a calcitonin-secreting PNET. We initiated treatment with long-acting SST analogs and peptide receptor radionuclide therapy (90Yttrium-DOTATOC) and achieved disease regression while maintaining a high quality of life. Functional PNETs that secrete calcitonin are exceedingly rare, but they are important to consider in the differential diagnosis of nonthyroid-mediated hypercalcitonemia or pancreatic tumors that present with diarrhea, as the management differs markedly from both MTC and other pancreatic malignancies.

  9. Gene Amplifications in Well-Differentiated Pancreatic Neuroendocrine Tumors Inactivate the p53 Pathway

    PubMed Central

    Hu, Wenwei; Feng, Zhaohui; Modica, Ippolito; Klimstra, David S.; Song, Lin; Allen, Peter J.; Brennan, Murray F.; Levine, Arnold J.; Tang, Laura H.

    2010-01-01

    Neuroendocrine tumors (NETs) comprise a group of rare tumors derived from the diffuse neuroendocrine system or islet endocrine cells of the pancreas. The molecular mechanisms underlying NETs are largely unknown. The tumor suppressor p53 plays a critical role in maintaining genomic stability and tumor prevention. The p53 pathway is tightly regulated by a number of proteins, among which MDM2, MDM4, and WIP1 are key negative regulators of p53 protein levels or activity. Aberrant activation of these negative regulators can attenuate the p53 function that serves as an important mechanism of tumorigenesis. In this study, several genetic alterations in pancreatic NETs were studied. These tumors exhibit various chromosomal aberrations throughout the whole genome as examined by array-based comparative genomic hybridization. Although p53 mutations are rare in NETs (<3%), this study presents evidence that the p53 pathway is altered in pancreatic NETs through aberrant activation of its negative regulators. A high percentage of pancreatic NETs contain extra gene copies of MDM2 (22%), MDM4 (30%), and WIP1 (51%), which are correlated with expression of corresponding mRNAs and proteins. In addition, there is a higher frequency (23% v. 15% in the control population) of the G/G genotype of MDM2 SNP309, a functional single-nucleotide polymorphism in the MDM2 gene that attenuates the function of the p53 protein. Overall, approximately 70% of pancreatic NETs have one or more of these genetic changes. These findings suggest that the negative regulation of p53 function could be an important mechanism for the initiation and/or progression of pancreatic NETs, and reactivation of p53 could be a potential therapeutic strategy for patients with this disease. PMID:20871795

  10. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein

    PubMed Central

    Kamphorst, Jurre J.; Nofal, Michel; Commisso, Cosimo; Hackett, Sean R.; Lu, Wenyun; Grabocka, Elda; Vander Heiden, Matthew G.; Miller, George; Drebin, Jeffrey A.; Bar-Sagi, Dafna; Thompson, Craig B.; Rabinowitz, Joshua D.

    2014-01-01

    Glucose and amino acids are key nutrients supporting cell growth. Amino acids are imported as monomers, but an alternative route induced by oncogenic KRAS involves uptake of extracellular proteins via macropinocytosis and subsequent lysosomal degradation of these proteins as a source of amino acids. In this study, we examined the metabolism of pancreatic ductal adenocarcinoma (PDAC), a poorly vascularized lethal KRAS-driven malignancy. Metabolomic comparisons of human PDAC and benign adjacent tissue revealed that tumor tissue was low in glucose, upper glycolytic intermediates, creatine phosphate and the amino acids glutamine and serine, two major metabolic substrates. Surprisingly, PDAC accumulated essential amino acids. Such accumulation could arise from extracellular proteins being degraded through macropinocytosis in quantities necessary to meet glutamine requirements, which in turn produces excess of most other amino acids. Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens. Moreover, in the presence of physiological albumin, we found that cultured murine PDAC cells grow indefinitely in media lacking single essential amino acids, and replicate once in the absence of free amino acids. Growth under these conditions was characterized by simultaneous glutamine depletion and essential amino acid accumulation. Overall, our findings argue that the scavenging of extracellular proteins is an important mode of nutrient uptake in PDAC. PMID:25644265

  11. Fluorescence laparoscopy imaging of pancreatic tumor progression in an orthotopic mouse model

    PubMed Central

    Tran Cao, Hop S.; Kaushal, Sharmeela; Lee, Claudia; Snyder, Cynthia S.; Thompson, Kari J.; Horgan, Santiago; Talamini, Mark A.; Hoffman, Robert M.

    2010-01-01

    Background The use of fluorescent proteins to label tumors is revolutionizing cancer research, enabling imaging of both primary and metastatic lesions, which is important for diagnosis, staging, and therapy. This report describes the use of fluorescence laparoscopy to image green fluorescent protein (GFP)-expressing tumors in an orthotopic mouse model of human pancreatic cancer. Methods The orthotopic mouse model of human pancreatic cancer was established by injecting GFP-expressing MiaPaCa-2 human pancreatic cancer cells into the pancreas of 6-week-old female athymic mice. On postoperative day 14, diagnostic laparoscopy using both white and fluorescent light was performed. A standard laparoscopic system was modified by placing a 480-nm short-pass excitation filter between the light cable and the laparoscope in addition to using a 2-mm-thick emission filter. A camera was used that allowed variable exposure time and gain setting. For mouse laparoscopy, a 3-mm 0° laparoscope was used. The mouse’s abdomen was gently insufflated to 2 mm Hg via a 22-gauge angiocatheter. After laparoscopy, the animals were sacrificed, and the tumors were collected and processed for histologic review. The experiments were performed in triplicate. Results Fluorescence laparoscopy enabled rapid imaging of the brightly fluorescent tumor in the pancreatic body. Use of the proper filters enabled simultaneous visualization of the tumor and the surrounding structures with minimal autofluorescence. Fluorescence laparoscopy thus allowed exact localization of the tumor, eliminating the need to switch back and forth between white and fluorescence lighting, under which the background usually is so darkened that it is difficult to maintain spatial orientation. Conclusion The use of fluorescence laparoscopy permits the facile, real-time imaging and localization of tumors labeled with fluorescent proteins. The results described in this report should have important clinical potential. PMID:20533064

  12. Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors.

    PubMed

    Fjällskog, Marie-Louise H; Lejonklou, Margareta H; Oberg, Kjell E; Eriksson, Barbro K; Janson, Eva T

    2003-04-01

    Molecular targeting with monoclonal antibodies and tyrosine kinase inhibitors is a novel approach to cancer treatment. We have examined the expression of molecular targets in patients with malignant endocrine pancreatic tumors, which is necessary to justify additional studies investigating the potential benefit from such treatment. Thirty-eight tumor tissues from malignant endocrine pancreatic tumors were examined with immunohistochemistry using specific polyclonal antibodies with regard to the expression pattern of platelet-derived growth factor receptors (PDGFRs) alpha and beta, c-kit, and epidermal growth factor receptor (EGFR). All 38 tissue specimens expressed PDGFRalpha on tumor cells, and 21 of 37 specimens (57%) expressed PDGFRalpha in tumor stroma (1 specimen was nonevaluable). Twenty-eight samples (74%) stained positive for PDGFRbeta on tumor cells, and 36 of 37 samples (97%) stained positive for PDGFRbeta in the stroma (1 specimen was nonevaluable). Thirty-five tumor tissues (92%) stained positive for c-kit, and 21 (55%) stained positive for EGFR on tumor cells. No differences were seen between syndromes or between poorly differentiated or well-differentiated tumors. Previous treatment did not influence expression pattern. Receptor expression pattern varied considerably between individuals. We have found that tyrosine kinase receptors PDGFRs alpha and beta, EGFR, and c-kit are expressed in more than half of the patients with endocrine pancreatic tumors. Because these receptors represent molecular targets for STI571 and ZD1839 (tyrosine kinase inhibitors) and IMC-C225 (a monoclonal antibody), we propose that patients suffering from EPTs might benefit from this new treatment strategy. However, because of great variability in receptor expression pattern, all patients' individual receptor expression should be examined.

  13. SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

    SciTech Connect

    Soltani, M; Bazmara, H; Sefidgar, M; Subramaniam, R; Rahmim, A

    2015-06-15

    Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm{sup 3}, were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm{sup 3}, was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm{sup 3}, the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic

  14. A Pancreatic Solid Pseudo-Papillary Tumor Detected After Abdominal Injury.

    PubMed

    Ishii, Atsushi; Yoshimura, Kazuko; Ideguchi, Hiroshi; Hirose, Shinichi

    2013-04-01

    Solid pseudo-papillary tumor (SPT) of the pancreas is a relatively benign tumor that is more frequently reported in females. Most patients usually present with abdominal pain or mass. We experienced the girl who identified SPT with the injury. We diagnosed SPT in a previously healthy 14-year-old Asian girl after abdominal injury. She experienced upper abdominal pain and vomiting after being hit by a basketball. Blood examination revealed a high serum amylase level. Abdominal radiography indicated abnormal bowel gases. Contrast-enhanced computed tomography revealed a smooth, peripheral and unilocular mass approximately 55 mm in diameter in the pancreatic tail. Based on these observations, acute pancreatitis complicated by a pancreatic mass was initially diagnosed. Therapy for acute pancreatitis was instituted, while we simultaneously investigated the mass. Levels of tumor markers were not profoundly elevated in serum. Dynamic contrast-enhanced magnetic resonance imaging (MRI) revealed moderate and gradual increase in contrast-enhanced imaging, consistent with findings of SPT of the pancreas. We thus elected surgical resection for her. Pathological examination of the surgical specimen confirmed our diagnosis of SPT. SPT of the pancreas should be considered as a differential diagnosis of acute abdomen disorders, especially in instances after minor abdominal injuries in young women, and diagnoses must be confirmed with MRIs.

  15. CA19-9: A promising tumor marker for pancreatic carcinoma

    SciTech Connect

    Sakahara, H.; Endo, K.; Nakajima, K.; Hidaka, A.; Nakashima, T.; Ohta, H.; Torizuka, K.; Naito, A.; Suzuki, T.

    1984-01-01

    In order to evaluate CA19-9 as a tumor marker for pancreatic carcinoma (PC), serum levels of CA19-9 were compared with those of CEA and elastase-1 in 56 patients, consisted of 43 cases with histologically proven adenocarcinomas and 13 cases with chronic pancreatitis. Serum levels were determined by using RIA kit obtained from CIS, France (CA19-9 and CEA) and Abbot (elastase-1). CA19-9 gave the highest accuracy among tumor markers the authors have studied and serum levels were markedly elevated over 100U/ml in 30 (70%) cases with PC, whereas none in chronic pancreatitis. CA19-9 values were closely related to the tumor size and the presence or absence of metastsis on CT findings. Small tumors of less than 3cm in diameter, although the site of tumor was limited to the head of the pancreas, showed positive results in 2 out of 5 cases. Furthermore, CA19-9 was at a level of less than 22U/ml in 98 normal controls and was found to be elevated in only 4 (3%) out of 124 patients with benign diseases, including liver diseases, gastric ulcer, cholelithiasis, and so on. These results indicate that CA19-9 is much better in diagnosis and management of PC than is CEA.

  16. A case report of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct.

    PubMed

    Okazaki, Mitsuyoshi; Makino, Isamu; Kitagawa, Hirohisa; Nakanuma, Shinichi; Hayashi, Hironori; Nakagawara, Hisatoshi; Miyashita, Tomoharu; Tajima, Hidehiro; Takamura, Hiroyuki; Ohta, Tetsuo

    2014-01-21

    We herein report a case of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct. A 76-year-old male was referred to our hospital for treatment of a pancreatic tumor. Preoperative examinations revealed a poorly defined tumor in the main pancreatic duct in the body of the pancreas, accompanied with severe dilatation of the main pancreatic duct, which was diagnosed as an intraductal papillary-mucinous neoplasm. We performed distal pancreatectomy and splenectomy. The pathological examination revealed that the tumor consisted of a mixture of anaplastic carcinoma (giant cell type) and adenocarcinoma in the pancreas. There was a papillary projecting tumor composed of anaplastic carcinoma in the dilated main pancreatic duct. The patient is now receiving chemotherapy because liver metastasis was detected 12 mo after surgery. In this case, we could observe a remarkable intraductal tumor growth into the main pancreatic duct. We also discuss the pathogenesis and characteristics of this rare tumor with specific tumor growth.

  17. Clinical impact of chemotherapy to improve tumor microenvironment of pancreatic cancer

    PubMed Central

    Tsuchikawa, Takahiro; Takeuchi, Shintaro; Nakamura, Toru; Shichinohe, Toshiaki; Hirano, Satoshi

    2016-01-01

    A perioperative multimodal strategy including combination chemotherapy and radiotherapy, in addition to surgical resection, has been acknowledged to improve patient prognosis. However chemotherapy has not been actively applied as an immunomodulating modality because of concerns about various immunosuppressive effects. It has recently been shown that certain chemotherapeutic agents could modify tumor microenvironment and host immune responses through several underlying mechanisms such as immunogenic cell death, local T-cell infiltration and also the eradication of immune-suppressing regulatory cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells. With the better understanding of the cell components in the tumor microenvironment and the effect of chemotherapy to improve tumor microenvironment, it has been gradually clear that the chemotherapeutic agents is two-edged sword to have both immune promoting and suppressing effects. The cellular components of the tumor microenvironment include infiltrating T lymphocytes, dendritic cells, regulatory T cells, tumor associated macrophages, myeloid derived suppressor cells and cancer associated fibroblasts. Based on the better understanding of tumor microenvironment following chemotherapy, the treatment protocol could be modified as personalized medicine and the prognosis of pancreas cancer would be more improved utilizing multimodal chemotherapy. Here we review the recent advances of chemotherapy to improve tumor microenvironment of pancreatic cancer, introducing the unique feature of tumor microenvironment of pancreatic cancer, interaction between anti-cancer reagents and these constituting cells and future prospects. PMID:27895816

  18. Clinical impact of chemotherapy to improve tumor microenvironment of pancreatic cancer.

    PubMed

    Tsuchikawa, Takahiro; Takeuchi, Shintaro; Nakamura, Toru; Shichinohe, Toshiaki; Hirano, Satoshi

    2016-11-15

    A perioperative multimodal strategy including combination chemotherapy and radiotherapy, in addition to surgical resection, has been acknowledged to improve patient prognosis. However chemotherapy has not been actively applied as an immunomodulating modality because of concerns about various immunosuppressive effects. It has recently been shown that certain chemotherapeutic agents could modify tumor microenvironment and host immune responses through several underlying mechanisms such as immunogenic cell death, local T-cell infiltration and also the eradication of immune-suppressing regulatory cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells. With the better understanding of the cell components in the tumor microenvironment and the effect of chemotherapy to improve tumor microenvironment, it has been gradually clear that the chemotherapeutic agents is two-edged sword to have both immune promoting and suppressing effects. The cellular components of the tumor microenvironment include infiltrating T lymphocytes, dendritic cells, regulatory T cells, tumor associated macrophages, myeloid derived suppressor cells and cancer associated fibroblasts. Based on the better understanding of tumor microenvironment following chemotherapy, the treatment protocol could be modified as personalized medicine and the prognosis of pancreas cancer would be more improved utilizing multimodal chemotherapy. Here we review the recent advances of chemotherapy to improve tumor microenvironment of pancreatic cancer, introducing the unique feature of tumor microenvironment of pancreatic cancer, interaction between anti-cancer reagents and these constituting cells and future prospects.

  19. Pancreatic Cancer Tumor Size on CT Scan Versus Pathologic Specimen: Implications for Radiation Treatment Planning

    SciTech Connect

    Arvold, Nils D.; Niemierko, Andrzej; Mamon, Harvey J.; Hong, Theodore S.

    2011-08-01

    Purpose: Pancreatic cancer primary tumor size measurements are often discordant between computed tomography (CT) and pathologic specimen after resection. Dimensions of the primary tumor are increasingly relevant in an era of highly conformal radiotherapy. Methods and Materials: We retrospectively evaluated 97 consecutive patients with resected pancreatic cancer at two Boston hospitals. All patients had CT scans before surgical resection. Primary endpoints were maximum dimension (in millimeters) of the primary tumor in any direction as reported by the radiologist on CT and by the pathologist for the resected gross fresh specimen. Endoscopic ultrasound (EUS) findings were analyzed if available. Results: Of the patients, 87 (90%) had preoperative CT scans available for review and 46 (47%) had EUS. Among proximal tumors (n = 69), 40 (58%) had pathologic duodenal invasion, which was seen on CT in only 3 cases. The pathologic tumor size was a median of 7 mm larger compared with CT size for the same patient (range, -15 to 43 mm; p < 0.0001), with 73 patients (84%) having a primary tumor larger on pathology than CT. Endoscopic ultrasound was somewhat more accurate, with pathologic tumor size being a median of only 5 mm larger compared with EUS size (range, -15 to 35 mm; p = 0.0003). Conclusions: Computed tomography scans significantly under-represent pancreatic cancer tumor size compared with pathologic specimens in resectable cases. We propose a clinical target volume expansion formula for the primary tumor based on our data. The high rate of pathologic duodenal invasion suggests a risk of duodenal undercoverage with highly conformal radiotherapy.

  20. Tumor suppressor Fbxw7 antagonizes WNT signaling by targeting β-catenin for degradation in pancreatic cancer.

    PubMed

    Jiang, Jian-Xin; Sun, Cheng-Yi; Tian, She; Yu, Chao; Chen, Mei-Yuan; Zhang, Hao

    2016-10-01

    Pancreatic cancer is one of the deadliest solid malignancies associated with aberrant Wnt signaling activation. Fbxw7 mutations have been implicated in the development of pancreatic cancer, whereas the exact mechanism of this ubiquitin ligase as a tumor suppressor remains unclear in pancreatic carcinogenesis. Here, we describe that Fbxw7 is downregulated upon pancreatic cancer development. Depletion of Fbxw7 results in tumor suppression in pancreatic cancer cells, while Fbxw7 overexpression inhibits pancreatic cancer cell proliferation and invasion. Considering the negative correlation between Fbxw7 and β-catenin, we find that Fbxw7 antagonizes Wnt signaling through targeting β-catenin for its degradation. Moreover, the inhibitory effect of Fbxw7 on pancreatic cancer cell proliferation is mainly executed by the destruction of the Wnt/β-catenin signaling pathway. We also reveal that c-myc, a widely accepted target of Fbxw7, is also transcriptionally regulated by the Fbxw7/β-catenin axis in pancreatic cancer cells. Collectively, our results demonstrate that Fbxw7 is a novel regulator of Wnt/β-catenin signaling-dependent regulation of pancreatic cancer cell growth and invasion, and inactivation of Fbxw7 in pancreatic cancer tissues might be the reason for the aberrant activation of Wnt signaling.

  1. Efficacy of liposomal curcumin in a human pancreatic tumor xenograft model: inhibition of tumor growth and angiogenesis.

    PubMed

    Ranjan, Amalendu P; Mukerjee, Anindita; Helson, Lawrence; Gupta, Rohan; Vishwanatha, Jamboor K

    2013-09-01

    Liposome-based drug delivery has been successful in the past decade, with some formulations being Food and Drug Administration (FDA)-approved and others in clinical trials around the world. The major disadvantage associated with curcumin, a potent anticancer agent, is its poor aqueous solubility and hence low systemic bioavailability. However, curcumin can be encapsulated into liposomes to improve systemic bioavailability. We determined the antitumor effects of a liposomal curcumin formulation against human MiaPaCa pancreatic cancer cells both in vitro and in xenograft studies. Histological sections were isolated from murine xenografts and immunohistochemistry was performed. The in vitro (IC50) liposomal curcumin proliferation-inhibiting concentration was 17.5 μM. In xenograft tumors in nude mice, liposomal curcumin at 20 mg/kg i.p. three-times a week for four weeks induced 42% suppression of tumor growth compared to untreated controls. A potent antiangiogenic effect characterized by a reduced number of blood vessels and reduced expression of vascular endothelial growth factor and annexin A2 proteins, as determined by immunohistochemistry was observed in treated tumors. These data clearly establish the efficacy of liposomal curcumin in reducing human pancreatic cancer growth in the examined model. The therapeutic curcumin-based effects, with no limiting side-effects, suggest that liposomal curcumin may be beneficial in patients with pancreatic cancer.

  2. Gender-Specific Transfusion Affects Tumor-Associated Neutrophil: Macrophage Ratios in Murine Pancreatic Adenocarcinoma

    PubMed Central

    Benson, Douglas D.; Kelher, Marguerite R.; Meng, Xianzhong; Fullerton, David A.; Lee, Joon H.; Silliman, Christopher C.

    2011-01-01

    Introduction Perioperative blood transfusion has been linked to decreased survival for pancreas cancer. Noting clinical data associating female blood products with increased morbidity, our lab has demonstrated that transfusion of female blood augments metastatic events compared to male blood in an immunocompetent murine pancreatic cancer model. It has been suggested that tumor-associated macrophages correlate with tumor progression by promoting angiogenesis. More recently, tumor-associated neutrophils have been implicated in aggressive tumor behavior. We hypothesize that differences in gender-specific transfusion-mediated pancreatic cancer progression are due to microenvironmental changes within the tumor. To test this hypothesis, we examined tumor-associated neutrophils and macrophage ratios in male and female mice with pancreatic cancer receiving blood transfusion from male or female donors. Methods C57/BL6 mice, age 7–9 weeks, underwent splenic inoculation with 2.5×105 PanO2 murine pancreatic adenocarcinoma cells. Mice were transfused on post-op day 7 with 1 ml/kg supernatant from day 42 male or female packed red cells. Necropsy was performed at 5 weeks or earlier for clinical deterioration, and tumors harvested. Frozen sections (5 μm) were stained for neutrophils and macrophages by immunofluorescence. Data were analyzed using ANOVA; p≤0.05 was used to determine significance; N≥3 per group. Results Clinically, male mice had greater morbidity and mortality than female mice when receiving female blood products, with roughened hair coat, development of ascites and death due to bowel obstruction. In evaluating the tumor microenvironment from mice receiving female blood products, male mice were noted to have a greater neutrophil to macrophage ratio than female mice, 0.176±0.028 vs. 0.073±0.012, p=0.03. When examining neutrophil to macrophage ratio in mice receiving male blood products, no difference was noted (p=0.48). Conclusions Male mice with pancreas

  3. Von Hippel Lindau disease with metastatic pancreatic neuroendocrine tumor causing ectopic Cushing's syndrome.

    PubMed

    Hatipoglu, Esra; Kepicoglu, Hasan; Rusen, Elif; Kabasakal, Levent; Gundogdu, Sadi; Kadioglu, Pinar

    2013-01-01

    We present a 39-year-old woman who was previously diagnosed with Von Hippel Lindau Disease (VHLD). She had surgery and radiotherapy for cranial hemangioblastoma (HA) 11 years ago and had unilateral adrenalectomy for pheochromocytoma in another hospital 6 month prior to her admission to our center. Moon face, buffalo hump, central obesity, progressive weight gain and menstrual irregularities persisted after adrenalectomy. Her laboratory results were consistent with ectopic Cushing's syndrome (ECS). A pancreatic solid mass with a nodule on the left lung were revealed upon computed tomography. In addition, Gallium-68 Somatostatin Receptor PET confirmed the pancreatic involvement and demonstrated additional lesions on the left lung and in the aortocaval lymphatic system on the right side, suggesting metastatic pancreatic neuroendocrine tumor (PNET). Peptide receptor radionuclide therapy (PRRT) with [177Lutetium-DOTA0,Tyr3] octreotate was performed on the patient, with no side effects observed. She was discharged from the hospital 10 days after the first cycle.

  4. Chondroitin sulfate proteoglycan CSPG4 as a novel hypoxia-sensitive marker in pancreatic tumors.

    PubMed

    Keleg, Shereen; Titov, Alexandr; Heller, Anette; Giese, Thomas; Tjaden, Christine; Ahmad, Sufian S; Gaida, Matthias M; Bauer, Andrea S; Werner, Jens; Giese, Nathalia A

    2014-01-01

    CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4) might circulate and reflect potential changes in CSPG4 tissue expression (pCSPG4) due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n = 83) and validation (n = 221) cohorts comprising donors (n = 11+26) and patients with chronic pancreatitis (n = 11+20) or neoplasms: benign (serous cystadenoma SCA, n = 13+20), premalignant (intraductal dysplastic IPMNs, n = 9+55), and malignant (IPMN-associated invasive carcinomas, n = 4+14; ductal adenocarcinomas, n = 35+86). Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n = 139), western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissue(high)/sera(low)-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct

  5. Chondroitin Sulfate Proteoglycan CSPG4 as a Novel Hypoxia-Sensitive Marker in Pancreatic Tumors

    PubMed Central

    Keleg, Shereen; Titov, Alexandr; Heller, Anette; Giese, Thomas; Tjaden, Christine; Ahmad, Sufian S.; Gaida, Matthias M.; Bauer, Andrea S.; Werner, Jens; Giese, Nathalia A.

    2014-01-01

    CSPG4 marks pericytes, undifferentiated precursors and tumor cells. We assessed whether the shed ectodomain of CSPG4 (sCSPG4) might circulate and reflect potential changes in CSPG4 tissue expression (pCSPG4) due to desmoplastic and malignant aberrations occurring in pancreatic tumors. Serum sCSPG4 was measured using ELISA in test (n = 83) and validation (n = 221) cohorts comprising donors (n = 11+26) and patients with chronic pancreatitis (n = 11+20) or neoplasms: benign (serous cystadenoma SCA, n = 13+20), premalignant (intraductal dysplastic IPMNs, n = 9+55), and malignant (IPMN-associated invasive carcinomas, n = 4+14; ductal adenocarcinomas, n = 35+86). Pancreatic pCSPG4 expression was evaluated using qRT-PCR (n = 139), western blot analysis and immunohistochemistry. sCSPG4 was found in circulation, but its level was significantly lower in pancreatic patients than in donors. Selective maintenance was observed in advanced IPMNs and PDACs and showed a nodal association while lacking prognostic relevance. Pancreatic pCSPG4 expression was preserved or elevated, whereby neoplastic cells lacked pCSPG4 or tended to overexpress without shedding. Extreme pancreatic overexpression, membranous exposure and tissuehigh/seralow-discordance highlighted stroma-poor benign cystic neoplasm. SCA is known to display hypoxic markers and coincide with von-Hippel-Lindau and Peutz-Jeghers syndromes, in which pVHL and LBK1 mutations affect hypoxic signaling pathways. In vitro testing confined pCSPG4 overexpression to normal mesenchymal but not epithelial cells, and a third of tested carcinoma cell lines; however, only the latter showed pCSPG4-responsiveness to chronic hypoxia. siRNA-based knockdowns failed to reduce the malignant potential of either normoxic or hypoxic cells. Thus, overexpression of the newly established conditional hypoxic indicator, CSPG4, is apparently non-pathogenic in pancreatic malignancies but might mark distinct epithelial

  6. Ki67 Scoring in Pancreatic Neuroendocrine Tumors By a New Method.

    PubMed

    Öztürk Sari, Şule; Taşkin, Orhun Çiğ; Yegen, Gülçin; Özlük, Yasemin; Güllüoğlu, Mine

    2016-07-06

    Ki67 scoring is required for the grading of pancreatic neuroendocrine tumors. Ongoing debate exists about the best scoring method in terms of accuracy and practicality. Manual counting of cells in camera-captured/printed images is a widely used and accepted method and considered the most reliable one among the manual methods. It requires counting 500 to 2000 cells to determine the Ki67 score accurately and it is time and energy consuming. We investigated the possibility of achieving the same results by counting only a particular fraction of tumor cells in a printed image in a series of 45 (24 grade 1 and 21 grade 2) pancreatic neuroendocrine tumors. After counting Ki67-positive tumor cells in the whole image, the tumor cells were counted within one-tenth of the same image with the aid of a previously prepared grid on an acetate sheet. The cell number obtained was multiplied by 10 to estimate the total cell count and the Ki67 score was calculated. The agreement between the results of the acetate grid and conventional whole-image counting method was assessed. Near-perfect agreement was achieved regarding the total cell count and Ki67 score. The agreement on tumor grade between the two methods was perfect. The time spent on the process was significantly less than that spent on the conventional method. Although it needs to be validated in a larger series, the acetate grid method might be considered an alternative method for Ki67 scoring in neuroendocrine tumors.

  7. MUC1 enhances tumor progression and contributes towards immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma

    PubMed Central

    Tinder, Teresa L.; Subramani, Durai B.; Basu, Gargi D.; Bradley, Judy M.; Schettini, Jorge; Million, Arefayene; Skaar, Todd

    2008-01-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune competent host. Significant enhancement in the development of pancreatic intraepithelial pre-neoplastic lesions (PanINs) and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and indoleamine 2,3, dioxygenase compared to PDA mice lacking MUC1, especially during early stages of tumor development. The increased pro-inflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease which in turn regulate the immune responses. Thus, the mouse model is ideally-suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

  8. MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

    PubMed

    Tinder, Teresa L; Subramani, Durai B; Basu, Gargi D; Bradley, Judy M; Schettini, Jorge; Million, Arefayene; Skaar, Todd; Mukherjee, Pinku

    2008-09-01

    MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer.

  9. Prognostication and response assessment in liver and pancreatic tumors: The new imaging

    PubMed Central

    De Robertis, Riccardo; Tinazzi Martini, Paolo; Demozzi, Emanuele; Puntel, Gino; Ortolani, Silvia; Cingarlini, Sara; Ruzzenente, Andrea; Guglielmi, Alfredo; Tortora, Giampaolo; Bassi, Claudio; Pederzoli, Paolo; D’Onofrio, Mirko

    2015-01-01

    Diffusion-weighted imaging (DWI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and perfusion computed tomography (CT) are technical improvements of morphologic imaging that can evaluate functional properties of hepato-bilio-pancreatic tumors during conventional MRI or CT examinations. Nevertheless, the term “functional imaging” is commonly used to describe molecular imaging techniques, as positron emission tomography (PET) CT/MRI, which still represent the most widely used methods for the evaluation of functional properties of solid neoplasms; unlike PET or single photon emission computed tomography, functional imaging techniques applied to conventional MRI/CT examinations do not require the administration of radiolabeled drugs or specific equipments. Moreover, DWI and DCE-MRI can be performed during the same session, thus providing a comprehensive “one-step” morphological and functional evaluation of hepato-bilio-pancreatic tumors. Literature data reveal that functional imaging techniques could be proposed for the evaluation of these tumors before treatment, given that they may improve staging and predict prognosis or clinical outcome. Microscopic changes within neoplastic tissues induced by treatments can be detected and quantified with functional imaging, therefore these techniques could be used also for post-treatment assessment, even at an early stage. The aim of this editorial is to describe possible applications of new functional imaging techniques apart from molecular imaging to hepatic and pancreatic tumors through a review of up-to-date literature data, with a particular emphasis on pathological correlations, prognostic stratification and post-treatment monitoring. PMID:26078555

  10. ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth.

    PubMed

    Rath, Nicola; Morton, Jennifer P; Julian, Linda; Helbig, Lena; Kadir, Shereen; McGhee, Ewan J; Anderson, Kurt I; Kalna, Gabriela; Mullin, Margaret; Pinho, Andreia V; Rooman, Ilse; Samuel, Michael S; Olson, Michael F

    2017-02-01

    Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a Kras(G12D)/p53(R172H) mouse PDAC model, was associated with reduced survival. Conditional ROCK1 or ROCK2 activation promoted invasive growth of mouse PDAC cells into three-dimensional collagen matrices by increasing matrix remodeling activities. RNA sequencing revealed a coordinated program of ROCK-induced genes that facilitate extracellular matrix remodeling, with greatest fold-changes for matrix metalloproteinases (MMPs) Mmp10 and Mmp13 MMP inhibition not only decreased collagen degradation and invasion, but also reduced proliferation in three-dimensional contexts. Treatment of Kras(G12D)/p53(R172H) PDAC mice with a ROCK inhibitor prolonged survival, which was associated with increased tumor-associated collagen. These findings reveal an ancillary role for increased ROCK signaling in pancreatic cancer progression to promote extracellular matrix remodeling that facilitates proliferation and invasive tumor growth.

  11. Lipocalin-2 Promotes Pancreatic Ductal Adenocarcinoma by Regulating Inflammation in the Tumor Microenvironment.

    PubMed

    Gomez-Chou, Sobeyda; Swidnicka-Siergiejko, Agnieszka; Badi, Niharika; Chavez-Tomar, Myrriah; Lesinski, Gregory B; Bekaii-Saab, Tanios; Farren, Matthew R; Mace, Thomas A; Schmidt, Carl; Liu, Yan; Deng, Defeng; Hwang, Rosa F; Zhou, Liran; Moore, Todd T; Chatterjee, Deyali; Wang, Huamin; Leng, Xiaohong; Arlinghaus, Ralph B; Logsdon, Craig D; Cruz-Monserrate, Zobeida

    2017-03-01

    Lipocalin-2 (LCN2) promotes malignant development in many cancer types. LCN2 is upregulated in patients with pancreatic ductal adenocarcinoma (PDAC) and in obese individuals, but whether it contributes to PDAC development is unclear. In this study, we investigated the effects of Lcn2 depletion on diet-induced obesity, inflammation and PDAC development. Mice with acinar cell-specific expression of KrasG12D were crossed with Lcn2-depleted animals and fed isocaloric diets with varying amounts of fat content. Pancreas were collected and analyzed for inflammation, pancreatic intraepithelial neoplasia (PanIN) and PDAC. We also used a syngeneic orthotopic PDAC mouse model to study tumor growth in the presence or absence of Lcn2 expression. In addition, to understand the mechanistic role of how LCN2 could be mediating PDAC, we studied LCN2 and its specific receptor solute carrier family 22 member 17 (SLC22A17) in human pancreatic cancer stellate cells (PSC), key mediators of the PDAC stroma. Depletion of Lcn2 diminished extracellular matrix deposition, immune cell infiltration, PanIN formation and tumor growth. Notably, it also increased survival in both obesity-driven and syngeneic orthotopic PDAC mouse models. LCN2 modulated the secretion of pro-inflammatory cytokines in PSC of the PDAC tumor microenvironment, while downregulation of LCN2-specific receptor SLC22A17 blocked these effects. Our results reveal how LCN2 acts in the tumor microenvironment links obesity, inflammation and PDAC development.

  12. Melatonin potentiates chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor cells.

    PubMed

    Uguz, Abdulhadi C; Cig, Bilal; Espino, Javier; Bejarano, Ignacio; Naziroglu, Mustafa; Rodríguez, Ana B; Pariente, José A

    2012-08-01

    Melatonin has antitumor activity via several mechanisms including its antiproliferative and proapoptotic effects in addition to its potent antioxidant action. Thus, melatonin has proven useful in the treatment of tumors in association with chemotherapeutic drugs. This study was performed to evaluate the effect of melatonin on the cytotoxicity and apoptosis induced by three different chemotherapeutic agents, namely 5-fluorouracil (5-FU), cisplatin, and doxorubicin in the rat pancreatic tumor cell line AR42J. We found that both melatonin and the three chemotherapeutic drugs induce a time-dependent decrease in AR42J cell viability, reaching the highest cytotoxic effect after 48 hr of incubation. Furthermore, melatonin significantly augmented the cytotoxicity of the chemotherapeutic agents. Consistently, cotreatment of AR42J cells with each of the chemotherapeutic agents in the presence of melatonin increased the population of apoptotic cells, elevated mitochondrial membrane depolarization, and augmented intracellular reactive oxygen species (ROS) production compared to treatment with each chemotherapeutic agent alone. These results provide evidence that in vitro melatonin enhances chemotherapy-induced cytotoxicity and apoptosis in rat pancreatic tumor AR42J cells and, therefore, melatonin may be potentially applied to pancreatic tumor treatment as a powerful synergistic agent in combination with chemotherapeutic drugs. © 2012 John Wiley & Sons A/S.

  13. Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis.

    PubMed

    Singh, Ajay P; Moniaux, Nicolas; Chauhan, Subhash C; Meza, Jane L; Batra, Surinder K

    2004-01-15

    The MUC4 mucin is a high molecular weight membrane-bound glycoprotein. It is aberrantly expressed in pancreatic tumors and tumor cell lines with no detectable expression in the normal pancreas. A progressive increase of MUC4 expression has also been observed in pancreatic intraepithelial neoplasia, suggesting its association with disease development. Here, we investigated the consequences of silencing MUC4 expression in an aggressive and highly metastatic pancreatic tumor cell line CD18/HPAF that expresses high levels of MUC4. The expression of MUC4 was down-regulated by the stable integration of a plasmid-construct expressing antisense-MUC4 RNA. A decrease in MUC4 expression, confirmed by Western blot and immunofluorescence analyses, resulted in diminished growth and clonogenic ability of antisense-MUC4-transfected (EIAS19) cells compared with parental, empty vector (ZEO) and sense transfected (ES6) control cells. In addition, EIAS19 cells displayed a significant decrease in tumor growth and metastatic properties when transplanted orthotopically into the immunodeficient mice. In vitro biological assays for motility, adhesion, and aggregation demonstrated a 3-fold decrease in motility of EIAS19 cells compared with control cells, whereas these cells adhered more and showed an increase in cellular aggregation. Interestingly, MUC4 down-regulation also correlated with the reduced expression of its putative interacting partner, HER2/neu, in antisense-MUC4-transfected cells. In conclusion, the present work demonstrates, for the first time, a direct association of the MUC4 mucin with the metastatic pancreatic cancer phenotype and provides experimental evidence for a functional role of MUC4 in altered growth and behavioral properties of the tumor cell.

  14. Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling

    PubMed Central

    Tan, Xiang-Lin; Bhattacharyya, Kalyan K.; Dutta, Shamit K.; Bamlet, William R.; Rabe, Kari G.; Wang, Enfeng; Smyrk, Thomas C.; Oberg, Ann L.; Petersen, Gloria M.; Mukhopadhyay, Debabrata

    2015-01-01

    Objectives To further elucidate anti-cancer mechanisms of metformin again pancreatic cancer, we evaluated inhibitory effects of metformin on pancreatic tumorigenesis in a genetically-engineered mouse model, and investigated its possible anti-inflammatory and anti-angiogenesis effects. Methods Six-week old LSL-KrasG12D/+;Trp53F2-10 mice (10 per group) were administered once daily intraperitoneally with saline (control) for one week or metformin (125 mg/kg) for one week (Met_1wk) or three weeks (Met_3wk) prior to tumor initiation. All mice continued with their respective injections for six weeks post-tumor initiation. Molecular changes were evaluated by quantitative polymerase chain reaction (PCR), immunohistochemistry, and Western blotting. Results At euthanasia, pancreatic tumor volume in Met_1wk (median, 181.8 mm3) and Met_3wk (median, 137.9 mm3) groups was significantly lower than the control group (median, 481.1 mm3) (P = 0.001 and 0.0009, respectively). No significant difference was observed between Met_1wk and Met_3wk groups (P = 0.51). These results were further confirmed using tumor weight and tumor burden measurements. Furthermore, metformin treatment decreased the phosphorylation of nuclear factor κB (NFκB) and signal transducer and activator of transcription 3 (STAT3) as well as the expression of Sp1 transcription factor and several NFκB-regulated genes. Conclusions Metformin may inhibit pancreatic tumorigenesis by modulating multiple molecular targets in inflammatory pathways. PMID:25875801

  15. Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages

    PubMed Central

    Chin, Shan M.; Vardam-Kaur, Trupti; Liu, Hao; Hato, Tai; Babykutty, Suboj; Chen, Ivy; Deshpande, Vikram; Jain, Rakesh K.; Fukumura, Dai

    2015-01-01

    Background Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose-lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. Methods/Results In overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-ß signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1β as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis. Conclusion Metformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight

  16. Integrated clinicopathological features and gene microarray analysis of pancreatic neuroendocrine tumors.

    PubMed

    Zhou, Huaqiang; Chen, Qinchang; Tan, Wulin; Qiu, Zeting; Li, Si; Song, Yiyan; Gao, Shaowei

    2017-08-20

    Pancreatic neuroendocrine tumors are relatively rare pancreatic neoplasms over the world. Investigations about molecular biology of PNETs are insufficient for nowadays. We aimed to explore the expression of messenger RNA and regulatory processes underlying pancreatic neuroendocrine tumors from different views. The expression profile of GSE73338 were downloaded, including samples with pancreatic neuroendocrine tumors. First, the Limma package was utilized to distinguish the differentially expressed messenger RNA. Gene Ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed to explore the functions and pathways of target genes. In addition, we constructed a protein-protein interaction network. NEK2, UBE2C, TOP2A and PPP1R1A were revealed with continuous genomic alterations in higher tumor stage. 91 up-regulated and 36 down-regulated genes were identified to be differentially expressed in malignant PNETs. Locomotory behavior was significantly enriched for biological processes of metastasis PNETs. GCGR and GNAS were identified as the hub of proteins in the protein-protein interaction sub-network of malignant PNETs. We showed the gene expression differences in PNETs according to different clinicopathological aspects. NEK2, UBE2C, TOP2A are positively associated with high tumor grade, and PPP1R1A negatively. GCGR and GNAS are regarded as the hub of the PPI sub-network. CXCR4 may affect the progression of PNETs via the CXCR4-CXCL12-CXCR7 chemokine receptor axis. However, more studies are required. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Perioperative high dose rate (HDR) brachytherapy in unresectable locally advanced pancreatic tumors

    PubMed Central

    Waniczek, Dariusz; Piecuch, Jerzy; Mikusek, Wojciech; Arendt, Jerzy; Białas, Brygida

    2011-01-01

    Purpose The aim of the study was to present an original technique of catheter implantation for perioperative HDR-Ir192 brachytherapy in patients after palliative operations of unresectable locally advanced pancreatic tumors and to estimate the influence of perioperative HDR-Ir192 brachytherapy on pain relief in terminal pancreatic cancer patients. Material and methods Eight patients with pancreatic tumors located in the head of pancreas underwent palliative operations with the use of HDR-Ir192 brachytherapy. All patients qualified for surgery reported pain of high intensity and had received narcotic painkillers prior to operation. During the last phase of the surgery, the Nucletron® catheters were implanted in patients to prepare them for later perioperative brachytherapy. Since the 6th day after surgery HDR brachytherapy was performed. Before each brachytherapy fraction the location of implants were checked using fluoroscopy. A fractional dose was 5 Gy and a total dose was 20 Gy in the area of radiation. A comparative study of two groups of patients (with and without brachytherapy) with stage III pancreatic cancer according to the TNM scale was taken in consideration. Results and Conclusions The authors claim that the modification of catheter implantation using specially designed cannula, facilitates the process of inserting the catheter into the tumor, shortens the time needed for the procedure, and reduces the risk of complications. Mean survival time was 5.7 months. In the group of performed brachytherapy, the mean survival time was 6.7 months, while in the group of no brachytherapy performed – 4.4 months. In the group of brachytherapy, only one patient increased the dose of painkillers in the last month of his life. Remaining patients took constant doses of medicines. Perioperative HDR-Ir192 brachytherapy could be considered as a practical application of adjuvant therapy for pain relief in patients with an advanced pancreatic cancer. PMID:27895674

  18. Perioperative high dose rate (HDR) brachytherapy in unresectable locally advanced pancreatic tumors.

    PubMed

    Waniczek, Dariusz; Piecuch, Jerzy; Rudzki, Marek; Mikusek, Wojciech; Arendt, Jerzy; Białas, Brygida

    2011-06-01

    The aim of the study was to present an original technique of catheter implantation for perioperative HDR-Ir192 brachytherapy in patients after palliative operations of unresectable locally advanced pancreatic tumors and to estimate the influence of perioperative HDR-Ir192 brachytherapy on pain relief in terminal pancreatic cancer patients. Eight patients with pancreatic tumors located in the head of pancreas underwent palliative operations with the use of HDR-Ir192 brachytherapy. All patients qualified for surgery reported pain of high intensity and had received narcotic painkillers prior to operation. During the last phase of the surgery, the Nucletron(®) catheters were implanted in patients to prepare them for later perioperative brachytherapy. Since the 6(th) day after surgery HDR brachytherapy was performed. Before each brachytherapy fraction the location of implants were checked using fluoroscopy. A fractional dose was 5 Gy and a total dose was 20 Gy in the area of radiation. A comparative study of two groups of patients (with and without brachytherapy) with stage III pancreatic cancer according to the TNM scale was taken in consideration. The authors claim that the modification of catheter implantation using specially designed cannula, facilitates the process of inserting the catheter into the tumor, shortens the time needed for the procedure, and reduces the risk of complications. Mean survival time was 5.7 months. In the group of performed brachytherapy, the mean survival time was 6.7 months, while in the group of no brachytherapy performed - 4.4 months. In the group of brachytherapy, only one patient increased the dose of painkillers in the last month of his life. Remaining patients took constant doses of medicines. Perioperative HDR-Ir192 brachytherapy could be considered as a practical application of adjuvant therapy for pain relief in patients with an advanced pancreatic cancer.

  19. CD14/TLR4 priming potentially recalibrates and exerts anti-tumor efficacy in tumor associated macrophages in a mouse model of pancreatic carcinoma

    PubMed Central

    Prakash, Hridayesh; Nadella, Vinod; Singh, Sandhya; Schmitz-Winnenthal, Hubertus

    2016-01-01

    Pancreatic cancer is the fourth major cause of cancer related deaths in the world and 5 year survival is below 5%. Among various tumor directed therapies, stimulation of Toll-like receptors (TLR) has shown promising effects in various tumor models. However, pancreatic cancer cells frequently express these receptors themselves and their stimulation (TLR 2 and/or 4 particularly) within tumor microenvironment is known to potentially enhance tumor cell proliferation and cancer progression. Consistent stimulation of tumor associated macrophages (TAMs), in particular with tumor derived TLR ligand within the tumor microenvironment promotes cancer related inflammation, which is sterile, non-immunogenic and carcinogenic in nature. In view of this, recalibrating of TAM has the potential to induce immunogenic inflammation. Consistent with this, we provide experimental evidence for the first time in this study that priming of TAMs with TLR4 ligend (LPS) alone or in combination with IFN-γ not only recalibrates pancreatic tumor cells induced M2 polarization, but also confers anti-tumor potential in TAMs. Most interestingly, reduced tumor growth in macrophage depleted animals suggests that macrophage directed approaches are important for the management of pancreatic tumors. PMID:27511884

  20. Review: the role of hyperthermia in treating pancreatic tumors.

    PubMed

    Roesch, Martin; Mueller-Huebenthal, Boris

    2015-03-01

    There is only marginal improvement in outcome of treating pancreatic cancer in the last two decades. Time to open up and have a fresh look at complementary adjuvant treatment options. Hyperthermia may be one such option. Hyperthermic intraperitoneal chemotherapy (HIPEC) predominantly as a intrasurgical procedure has already proved its justification. Non-invasive loco regional hyperthermia as complement to either chemo or radiation has not yet reached a comparable status of evidence. However the potential to eventually grow into such evidence is already clearly observable. This review presents the various methodologies available for hyperthermia, covers the initial clinical data that has been published and gives an outlook to what can be expected in the next 2-3 years to come. Hyperthermia has the potential to significantly prolong life expectancies and this while maintaining a satisfying quality of life!

  1. Management of the Primary Tumor and Limited Metastases in Patients With Metastatic Pancreatic Cancer.

    PubMed

    Herman, Joseph M; Hoffman, John P; Thayer, Sarah P; Wolff, Robert A

    2015-05-01

    New combinations of cytotoxic chemotherapy have been proven to increase response rates and survival times compared with single-agent gemcitabine for patients with metastatic pancreatic cancer. These responses have been dramatic for a subset of patients, therefore raising questions about the management of limited metastatic disease with surgery or other ablative methods. Similarly, for patients having a complete radiographic response to chemotherapy in the metastatic compartment, whether to consider local therapy in the form of radiation or surgery for the primary tumor is now an appropriate question. Therefore, collaboration among experts in surgery, medical oncology, and radiation oncology has led to the development of guiding principles for local therapies to the primary intact pancreatic tumor for patients with limited metastatic disease and those who have had a significant response after systemic therapy.

  2. Imaging Tumor Variation in Response to Photodynamic Therapy in Pancreatic Cancer Xenograft Models

    SciTech Connect

    Samkoe, Kimberley S.; Chen, Alina; Rizvi, Imran; O'Hara, Julia A.; Hoopes, P. Jack; Pereira, Stephen P.; Hasan, Tayyaba; Pogue, Brian W.

    2010-01-15

    Purpose: A treatment monitoring study investigated the differential effects of orthotopic pancreatic cancer models in response to interstitial photodynamic therapy (PDT), and the validity of using magnetic resonance imaging as a surrogate measure of response was assessed. Methods and Materials: Different orthotopic pancreatic cancer xenograft models (AsPC-1 and Panc-1) were used to represent the range of pathophysiology observed in human beings. Identical dose escalation studies (10, 20, and 40J/cm) using interstitial verteporfin PDT were performed, and magnetic resonance imaging with T2-weighted and T1-weighted contrast were used to monitor the total tumor volume and the vascular perfusion volume, respectively. Results: There was a significant amount of necrosis in the slower-growing Panc-1 tumor using high light dose, although complete necrosis was not observed. Lower doses were required for the same level of tumor kill in the faster-growing AsPC-1 cell line. Conclusions: The tumor growth rate and vascular pattern of the tumor affect the optimal PDT treatment regimen, with faster-growing tumors being relatively easier to treat. This highlights the fact that therapy in human beings shows a heterogeneous range of outcomes, and suggests a need for careful individualized treatment outcomes assessment in clinical work.

  3. Everolimus and pancreatic neuroendocrine tumors (PNETs): Activity, resistance and how to overcome it.

    PubMed

    Capozzi, Monica; Caterina, Ieranò; De Divitiis, Chiara; von Arx, Claudia; Maiolino, Piera; Tatangelo, Fabiana; Cavalcanti, Ernesta; Di Girolamo, Elena; Iaffaioli, Rosario Vincenzo; Scala, Stefania; Tafuto, Salvatore

    2015-09-01

    Neuroendocrine tumors (NET) are rare malignancies, with the most common site of origin being from the gastrointestinal tract, particularly the pancreas, small bowel and appendix. Pancreatic neuroendocrine tumors (PNETs) can be functional, hormone secreting tumors, and can have distinctive symptoms leading to the diagnosis. In contrast nonfunctional tumors, the majority of PNETs, usually present later either incidentally or due to tumor bulk symptoms. Currently Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is the most promising drug for patients with unresectable, metastatic disease, in progressive well-differentiated PNETs and many studies are ongoing to demonstrate its effects on the other neuroendocrine histotipes. Food and Drug Administration (FDA) and European Medicines Agency (EMA) registered Everolimus in advanced/metastatic breast cancer, in advanced/metastatic renal cell carcinoma and in well/moderately differentiated pancreatic neuroendocrine tumors. Nevertheless only a subset of patients respond to the therapy due to the development of drug resistance. Thus the powerful Everolimus antitumor activity have prompted extensive efforts to overcome drug resistance and to maximize clinical benefit. In this review we aim to summarize current knowledge on mechanisms of Everolimus and other mTOR inhibitors molecules resistance with the intent to overcome it.

  4. Induction of Apoptosis in Tumor-Associated Endothelial Cells and Therapy of Orthotopic Human Pancreatic Carcinoma in Nude Mice1

    PubMed Central

    Yokoi, Kenji; Kim, Sun-Jin; Thaker, Premal; Yazici, Sertac; Nam, Do-Hyun; He, Junqin; Sasaki, Takamitsu; Chiao, Paul J; Sclabas, Guido M; Abbruzzese, James L; Hamilton, Stanley R; Fidler, Isaiah J

    2005-01-01

    Abstract Although gemcitabine has been accepted as the first-line chemotherapeutic reagent for advanced pancreatic cancer, improvement of response rate and survival is not sufficient and patients often develop resistance. We hypothesized that the inhibition of phosphorylation of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) on tumor cells and tumor-associated endothelial cells, combined with gemcitabine, would overcome the resistance to gemcitabine in orthotopic pancreatic tumor animal model. L3.6pl, human pancreatic cancer cells growing in the pancreas, and tumor-associated endothelial cells in microorgan environment highly expressed phosphorylated EGFR, VEGFR, and Akt, which regulates antiapoptotic mechanism. Oral administration of AEE788 (dual tyrosine kinase inhibitor against EGFR and VEGFR) inhibited the phosphorylation of EGFR, VEGFR, and Akt on tumor-associated endothelial cells as well as tumor cells. Although intraperitoneal (i.p.) injection of gemcitabine showed limited inhibitory effect on tumor growth, combination with AEE788 and gemcitabine produced nearly 95% inhibition of tumor growth in parallel with a high level of apoptosis on tumor cells and tumor-associated endothelial cells, and decreased microvascular density and proliferation rate. Collectively, these data indicate that dual inhibition of phosphorylation of EGFR and VEGFR, in combination with gemcitabine, produces apoptosis of tumor-associated endothelial cells and significantly suppresses human pancreatic cancer in nude mice. PMID:16026649

  5. MUC1-specific CTLs are non-functional within a pancreatic tumor microenvironment.

    PubMed

    Mukherjee, P; Ginardi, A R; Madsen, C S; Tinder, T L; Jacobs, F; Parker, J; Agrawal, B; Longenecker, B M; Gendler, S J

    2001-01-01

    Pancreatic cancer is a highly aggressive, treatment refractory disease and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas over-express altered forms of a tumor-associated antigen, MUC1 (an epithelial mucin glycoprotein), which is a target for immunotherapy. Using a clinically relevant mouse model of pancreas cancer that demonstrates peripheral and central tolerance to human MUC1 and develops spontaneous tumors of the pancreas, we have previously reported the presence of functionally active, low affinity, MUC1-specific precursor cytotoxic T cells (pCTLs). Hypothesis for this study is that MUC1-based immunization may enhance the low level MUC1-specific immunity that may lead to an effective anti-tumor response. Data demonstrate that MUC1 peptide-based immunization elicits mature MUC1-specific CTLs in the peripheral lymphoid organs. The mature CTLs secrete IFN-gamma and are cytolytic against MUC1-expressing tumor cells in vitro. However, active CTLs that infiltrate the pancreas tumor microenvironment become cytolytically anergic and are tolerized to MUC1 antigen, allowing the tumor to grow. We demonstrate that the CTL tolerance could be reversed at least in vitro with the use of anti-CD40 co-stimulation. The pancreas tumor cells secrete immunosuppressive cytokines, including IL-10 and TGF-beta that are partly responsible for the down-regulation of CTL activity. In addition, they down-regulate their MHC class I molecules to avoid immune recognition. CD4+ CD25+ T regulatory cells, which secrete IL-10, were also found in the tumor environment. Together these data indicate the use of several immune evasion mechanisms by tumor cells to evade CTL killing. Thus altering the tumor microenvironment to make it more conducive to CTL killing may be key in developing a successful anti-cancer immunotherapy.

  6. High Rab11-FIP4 expression predicts poor prognosis and exhibits tumor promotion in pancreatic cancer

    PubMed Central

    He, Yun; Ye, Mengsi; Zhou, Lingling; Shan, Yunfeng; Lu, Guangrong; Zhou, Yuhui; Zhong, Jinwei; Zheng, Jihang; Xue, Zhanxiong; Cai, Zhenzhai

    2017-01-01

    Some studies have demonstrated that Rab11-family interacting proteins (Rab11-FIPs) are connected with the tumorigenesis, and they may act as tumor promoters in some cancers. The clinicopathological significance of Rab11-family interacting protein 4 (Rab11-FIP4) expression and its possible effects on pancreatic cancer (PC) are still undiscovered. In this study, Rab11-FIP4 protein expression level in 60 PC specimens and pair-matched non-cancerous samples were detected by immunohistochemistry analysis. The results were analysed and compared with each patients' clinical data. Rab11-FIP4 expression in PC tissues increased significantly more than that of adjacent non-cancerous tissues (P=0.0001). Overexpression of Rab11-FIP4 in the PC tissues was significantly related to tumor size (P=0.0001), histological grade (P=0.028), metastasis (P=0.001) and TNM stage (P=0.004) but not with age (P=0.832), gender (P=0.228) or tumor site (P=0.875). Kaplan-Meier survival analysis showed that overexpression of Rab11-FIP4 was significantly related to overall survival time (P=0.0036). In addition, Rab11-FIP4 in PANC-1 pancreatic cancer cells were successfully knocked-out using the CRISPR/Cas9 system. Rab11-FIP4 knockout in PANC-1 cells inhibited cell growth, invasion and metastasis, and arrested cell cycle progression, but did not alter apoptosis. Our findings suggest that overexpression of Rab11-FIP4 predicts poor clinical outcomes for pancreatic cancer and contributes to pancreatic tumor progression. PMID:28035375

  7. SOX15 is a candidate tumor suppressor in pancreatic cancer with a potential role in Wnt/β-catenin signaling.

    PubMed

    Thu, K L; Radulovich, N; Becker-Santos, D D; Pikor, L A; Pusic, A; Lockwood, W W; Lam, W L; Tsao, M-S

    2014-01-16

    Pancreatic cancer is among the top five deadliest cancers in developed countries. Better knowledge of the molecular mechanisms contributing to its tumorigenesis is imperative to improve patient prognosis. Identification of novel tumor suppressor genes (TSGs) in pancreatic cancer will reveal new mechanisms of pathway deregulation and will ultimately help improve our understanding of this aggressive disease. According to Knudson's two-hit model, TSGs are classically disrupted by two concerted genetic events. In this study, we combined DNA methylation profiling with copy number and mRNA expression profiling to identify novel TSGs in a set of 20 pancreatic cancer cell lines. These data sets were integrated for each of ∼12 000 genes in each cell line enabling the elucidation of those genes that undergo DNA hypermethylation, copy-number loss and mRNA downregulation simultaneously in multiple cell lines. Using this integrative genomics strategy, we identified SOX15 (sex determining region Y-box 15) as a candidate TSG in pancreatic cancer. Expression of SOX15 in pancreatic cancer cell lines with undetectable expression resulted in reduced viability of cancer cells both in vitro and in vivo demonstrating its tumor suppressive capability. We also found reduced expression, homozygous deletion and aberrant DNA methylation of SOX15 in clinical pancreatic tumor data sets. Furthermore, we deduced a novel role for SOX15 in suppressing the Wnt/β-catenin signaling pathway, which we hypothesize is a pathway through which SOX15 may exert its tumor suppressive effects in pancreatic cancer.

  8. Pancreatitis

    MedlinePlus

    ... removal is sometimes performed along with a sphincterotomy. Stent placement. Using the endoscope, the doctor places a ... a narrowed pancreatic or bile duct. A temporary stent may be placed for a few months to ...

  9. Tumor tracking and motion compensation with an adaptive tumor tracking system (ATTS): system description and prototype testing.

    PubMed

    Wilbert, Jürgen; Meyer, Jürgen; Baier, Kurt; Guckenberger, Matthias; Herrmann, Christian; Hess, Robin; Janka, Christian; Ma, Lei; Mersebach, Torben; Richter, Anne; Roth, Michael; Schilling, Klaus; Flentje, Michael

    2008-09-01

    A novel system for real-time tumor tracking and motion compensation with a robotic HexaPOD treatment couch is described. The approach is based on continuous tracking of the tumor motion in portal images without implanted fiducial markers, using the therapeutic megavoltage beam, and tracking of abdominal breathing motion with optical markers. Based on the two independently acquired data sets the table movements for motion compensation are calculated. The principle of operation of the entire prototype system is detailed first. In the second part the performance of the HexaPOD couch was investigated with a robotic four-dimensional-phantom capable of simulating real patient tumor trajectories in three-dimensional space. The performance and limitations of the HexaPOD table and the control system were characterized in terms of its dynamic behavior. The maximum speed and acceleration of the HexaPOD were 8 mm/s and 34.5 mm/s2 in the lateral direction, and 9.5 mm/s and 29.5 mm/s2 in longitudinal and anterior-posterior direction, respectively. Base line drifts of the mean tumor position of realistic lung tumor trajectories could be fully compensated. For continuous tumor tracking and motion compensation a reduction of tumor motion up to 68% of the original amplitude was achieved. In conclusion, this study demonstrated that it is technically feasible to compensate breathing induced tumor motion in the lung with the adaptive tumor tracking system.

  10. Characterization of a pancreatic islet cell tumor in a polar bear (Ursus maritimus).

    PubMed

    Fortin, Jessica S; Benoit-Biancamano, Marie-Odile

    2014-01-01

    Herein, we report a 25-year-old male polar bear suffering from a pancreatic islet cell tumor. The aim of this report is to present a case of this rare tumor in a captive polar bear. The implication of potential risk factors such as high carbohydrate diet or the presence of amyloid fibril deposits was assessed. Necropsy examination revealed several other changes, including nodules observed in the liver, spleen, pancreas, intestine, and thyroid glands that were submitted for histopathologic analysis. Interestingly, the multiple neoplastic nodules were unrelated and included a pancreatic islet cell tumor. Immunohistochemistry of the pancreas confirmed the presence of insulin and islet amyloid polypeptide (IAPP) within the pancreatic islet cells. The IAPP gene was extracted from the paraffin-embedded liver tissue and sequenced. IAPP cDNA from the polar bear exhibits some differences as compared to the sequence published for several other species. Different factors responsible for neoplasms in bears such as diet, infectious agents, and industrial chemical exposure are reviewed. This case report raised several issues that further studies may address by evaluating the prevalence of cancers in captive or wild animals. © 2014 Wiley Periodicals, Inc.

  11. Tumor-specific gene therapy for pancreatic cancer using human neural stem cells encoding carboxylesterase

    PubMed Central

    Choi, Seon-A; Yoon, Seung-Bin; Kim, Seung U.; Lee, Hong J.

    2016-01-01

    Advanced pancreatic cancer is one of the most lethal malignant human diseases lacking effective treatment. Its extremely low survival rate necessitates development of novel therapeutic approach. Human neural stem cells (NSCs) are known to have tumor-tropic effect. We genetically engineered them to express rabbit carboxyl esterase (F3.CE), which activates prodrug CPT-11(irinotecan) into potent metabolite SN-38. We found significant inhibition of the growth of BxPC3 human pancreatic cancer cell line in vitro by F3.CE in presence of CPT-11. Apoptosis was also markedly increased in BxPC3 cells treated with F3.CE and CPT-11. The ligand VEGF and receptor VEGF-1(Flt1) were identified to be the relevant tumor-tropic chemoattractant. We confirmed in vivo that in mice injected with BxPC3 on their skin, there was significant reduction of tumor size in those treated with both F3.CE and BxPC3 adjacent to the cancer mass. Administration of F3.CE in conjunction with CPT-11 could be a new possibility as an effective treatment regimen for patients suffering from advanced pancreatic cancer. PMID:27659534

  12. Tumor-specific gene therapy for pancreatic cancer using human neural stem cells encoding carboxylesterase.

    PubMed

    Choi, Sung S; Yoon, Kichul; Choi, Seon-A; Yoon, Seung-Bin; Kim, Seung U; Lee, Hong J

    2016-11-15

    Advanced pancreatic cancer is one of the most lethal malignant human diseases lacking effective treatment. Its extremely low survival rate necessitates development of novel therapeutic approach. Human neural stem cells (NSCs) are known to have tumor-tropic effect. We genetically engineered them to express rabbit carboxyl esterase (F3.CE), which activates prodrug CPT-11(irinotecan) into potent metabolite SN-38. We found significant inhibition of the growth of BxPC3 human pancreatic cancer cell line in vitro by F3.CE in presence of CPT-11. Apoptosis was also markedly increased in BxPC3 cells treated with F3.CE and CPT-11. The ligand VEGF and receptor VEGF-1(Flt1) were identified to be the relevant tumor-tropic chemoattractant. We confirmed in vivo that in mice injected with BxPC3 on their skin, there was significant reduction of tumor size in those treated with both F3.CE and BxPC3 adjacent to the cancer mass. Administration of F3.CE in conjunction with CPT-11 could be a new possibility as an effective treatment regimen for patients suffering from advanced pancreatic cancer.

  13. Schwann Cells Increase Prostate and Pancreatic Tumor Cell Invasion Using Laminin Binding A6 Integrin.

    PubMed

    Sroka, Isis C; Chopra, Harsharon; Das, Lipsa; Gard, Jaime M C; Nagle, Raymond B; Cress, Anne E

    2016-02-01

    Human pancreatic and prostate cancers metastasize along nerve axons during perineural invasion. The extracellular matrix laminin class of proteins is an abundant component of both myelinated and non-myelinated nerves. Analysis of human pancreatic and prostate tissue revealed both perineural and endoneural invasion with Schwann cells surrounded or disrupted by tumor, respectively. Tumor and nerve cell co-culture conditions were used to determine if myelinating or non-myelinating Schwann cell (S16 and S16Y, respectively) phenotype was equally likely to promote integrin-dependent cancer cell invasion and migration on laminin. Conditioned medium from S16 cells increased tumor cell (DU145, PC3, and CFPAC1) invasion into laminin approximately 1.3-2.0 fold compared to fetal bovine serum (FBS) treated cells. Integrin function (e.g., ITGA6p formation) increased up to 1.5 fold in prostate (DU145, PC3, RWPE-1) and pancreatic (CFPAC1) cells, and invasion was dependent on ITGA6p formation and ITGB1 as determined by function-blocking antibodies. In contrast, conditioned medium isolated from S16Y cells (non-myelinating phenotype) decreased constitutive levels of ITGA6p in the tumor cells by 50% compared to untreated cells and decreased ITGA6p formation 3.0 fold compared to S16 treated cells. Flow cytometry and western blot analysis revealed loss of ITGA6p formation as reversible and independent of overall loss of ITGA6 expression. These results suggest that the myelinating phenotype of Schwann cells within the tumor microenvironment increased integrin-dependent tumor invasion on laminin. © 2015 Wiley Periodicals, Inc.

  14. How reliable is the Ki-67 cytological index in grading pancreatic neuroendocrine tumors? A meta-analysis.

    PubMed

    Li, Jun; Lin, Jin Ping; Shi, Liu Hong; Wang, Wei Jia; Li, Ai Qing; Si, Jian Min; Chen, Shu Jie

    2016-02-01

    To investigate the accuracy of the cytological Ki-67 index in distinguishing intermediate and high-grade (G2 + G3) from low-grade (G1) pancreatic neuroendocrine tumors (PNETs). Two investigators independently searched databases to identify eligible studies using the following term: ('Ki-67') AND ('pancreatic endocrine tumor' OR 'pancreatic neuroendocrine tumor' OR 'pancreatic endocrine tumour' OR 'pancreatic neuroendocrine tumour' OR 'pancreatic endocrine tumors' OR 'pancreatic neuroendocrine tumors' OR 'pancreatic endocrine tumours' OR 'pancreatic neuroendocrine tumours'), and meta-analysis was performed to calculate the pooled sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). A total of 263 lesions from 13 studies were included in the study. The pooled sensitivity and specificity of Ki-67 (cut-off value: 2%) in the differential diagnosis of G2 + G3 from G1 PNETs were 64% and 87%, respectively. The pooled PLR, NLR and DOR were 3.96, 0.42 and 11.21, respectively. The area under the summary receiver operating characteristic curve (AUROC) was 0.8397. While the cut-off value of Ki-67 index was set as 5%, the sensitivity and specificity were increased up to 69% and 93%, respectively, and the AUROC was increased to 0.955. The cytological Ki-67 index is very useful in distinguishing intermediate and high-grade from low-grade PNETs, and a cut-off value of 5% had a better predictive value compared with that of 2%. © 2016 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

  15. [A Case of Unresectable Advanced Rectal Cancer with a Pancreatic Tumor That Was Successfully Treated with FOLFIRINOX].

    PubMed

    Yabe, Nobushige; Murai, Shinji; Ozawa, Hiroki; Yokose, Takahiro; Oto, Ippei; Yoshikawa, Takahisa; Kitasato, Kenjiro; Shimizu, Hirotomo; Kojima, Kenji; Hasegawa, Hirotoshi; Kitagawa, Yuko

    2016-11-01

    A 72-year-old man was admitted to our hospital department in September 2014 because of a positive fecal occult blood test.Colonoscopy showed a type 2 tumor in half of the AV 15 cm rectosigmoid colon.Histology of the biopsy indicated a moderately differentiated adenocarcinoma, and the RAS gene test found wild type.On CT examination, there were multiple liver lung metastases and a 30mm diameter tumor with pancreatic duct extension to the pancreatic body.A PET-CT examination had a high SUVmax at the same site.Because of the location of the tumor EUS-FNA was not used.However, the possibility of pancreatic body cancer could not be denied after the CT examination.Treatment by radical resection was impossible because of the spread of the cancer so we selected chemotherapy.Undeniable pancreatic metastasis of rectal cancer, pancreatic cancer was used as a prognostic factor as double cancer of rectal cancer and pancreatic cancer, from that UGT1A1 test side effects appearance was a low-risk decision, was selected FOLFIRINOX in the treatment regimen.After 25 cycles, the pancreatic body tumor and liver metastases and also the primary tumor were reduced, the multiple lung metastases disappeared, and disease control was good.Side effects were diarrhea on the day of administration of irinotecan, but this was controllable by administering oral loperamide when starting the infusion.Grade 3 or more peripheral neuropathy has not developed, and this regimen is continuing.Pancreatic cancer is a solid cancer with a poor prognosis; if you do not reach the tissue diagnosis of metastatic pancreatic cancer, was a case in which no choice but to select a regimen to carcinoma of the prognostic.

  16. Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer

    PubMed Central

    Kang, Rui; Xie, Yangchun; Zhang, Qiuhong; Hou, Wen; Jiang, Qingping; Zhu, Shan; Liu, Jinbao; Zeng, Dexing; Wang, Haichao; Bartlett, David L; Billiar, Timothy R; Zeh, Herbert J; Lotze, Michael T; Tang, Daolin

    2017-01-01

    Pancreatic ductal adenocarcinoma (PDAC) driven by oncogenic K-Ras remains among the most lethal human cancers despite recent advances in modern medicine. The pathogenesis of PDAC is partly attributable to intrinsic chromosome instability and extrinsic inflammation activation. However, the molecular link between these two events in pancreatic tumorigenesis has not yet been fully established. Here, we show that intracellular high mobility group box 1 (HMGB1) remarkably suppresses oncogenic K-Ras-driven pancreatic tumorigenesis by inhibiting chromosome instability-mediated pro-inflammatory nucleosome release. Conditional genetic ablation of either single or both alleles of HMGB1 in the pancreas renders mice extremely sensitive to oncogenic K-Ras-driven initiation of precursor lesions at birth, including pancreatic intraepithelial neoplasms, intraductal papillary mucinous neoplasms, and mucinous cystic neoplasms. Loss of HMGB1 in the pancreas is associated with oxidative DNA damage and chromosomal instability characterized by chromosome rearrangements and telomere abnormalities. These lead to inflammatory nucleosome release and propagate K-Ras-driven pancreatic tumorigenesis. Extracellular nucleosomes promote interleukin 6 (IL-6) secretion by infiltrating macrophages/neutrophils and enhance oncogenic K-Ras signaling activation in pancreatic lesions. Neutralizing antibodies to IL-6 or histone H3 or knockout of the receptor for advanced glycation end products all limit K-Ras signaling activation, prevent cancer development and metastasis/invasion, and prolong animal survival in Pdx1-Cre;K-RasG12D/+;Hmgb1−/− mice. Pharmacological inhibition of HMGB1 loss by glycyrrhizin limits oncogenic K-Ras-driven tumorigenesis in mice under inflammatory conditions. Diminished nuclear and total cellular expression of HMGB1 in PDAC patients correlates with poor overall survival, supporting intracellular HMGB1 as a novel tumor suppressor with prognostic and therapeutic relevance in

  17. New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies.

    PubMed

    Schmitt, Anja M; Marinoni, Ilaria; Blank, Annika; Perren, Aurel

    2016-09-01

    The recent findings on the roles of death-associated protein 6/α-thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a cross-species study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs.

  18. Three-Dimensional Motion of Liver Tumors Using Cine-Magnetic Resonance Imaging

    SciTech Connect

    Kirilova, Anna Lockwood, Gina; Choi, Perry; Bana, Neelufer; Haider, Masoom A.; Brock, Kristy K.; Eccles, Cynthia; Dawson, Laura A.

    2008-07-15

    Purpose: To measure the three-dimensional motion of liver tumors using cine-magnetic resonance imaging (MRI) and compare it to the liver motion assessed using fluoroscopy. Methods and Materials: Liver and liver tumor motion were investigated in the first 36 patients with primary (n = 20) and metastatic (n = 16) liver cancer accrued to our Phase I stereotactic radiotherapy study. At simulation, all patients underwent anteroposterior fluoroscopy, and the maximal diaphragm excursion in the craniocaudal (CC) direction was observed. Cine-MRI using T{sub 2}-weighted single shot fast spin echo sequences were acquired in three orthogonal planes during free breathing through the centroid of the most dominant liver tumor. ImageJ software was used to measure the maximal motion of the tumor edges in each plane. The intra- and interobserver reproducibility was also quantified. Results: The average CC motion of the liver at fluoroscopy was 15 mm (range, 5-41). On cine-MRI, the average CC tumor motion was 15.5 mm (range, 6.9-35.4), the anteroposterior motion was 10 mm (range, 3.7-21.6), and the mediolateral motion was 7.5 mm (range, 3.8-14.8). The fluoroscopic CC diaphragm motion did not correlate well with the MRI CC tumor motion (r = 0.25). The mean intraobserver error was <2 mm in the CC, anteroposterior, and mediolateral directions, and 90% of measurements between observers were within 3 mm. Conclusions: The results of our study have shown that cine-MRI can be used to directly assess liver tumor motion in three dimensions. Tumor motion did not correlate well with the diaphragm motion measured using kilovoltage fluoroscopy. The tumor motion data from cine-MRI can be used to facilitate individualized planning target volume margins to account for breathing motion.

  19. Three-dimensional motion of liver tumors using cine-magnetic resonance imaging.

    PubMed

    Kirilova, Anna; Lockwood, Gina; Choi, Perry; Bana, Neelufer; Haider, Masoom A; Brock, Kristy K; Eccles, Cynthia; Dawson, Laura A

    2008-07-15

    To measure the three-dimensional motion of liver tumors using cine-magnetic resonance imaging (MRI) and compare it to the liver motion assessed using fluoroscopy. Liver and liver tumor motion were investigated in the first 36 patients with primary (n = 20) and metastatic (n = 16) liver cancer accrued to our Phase I stereotactic radiotherapy study. At simulation, all patients underwent anteroposterior fluoroscopy, and the maximal diaphragm excursion in the craniocaudal (CC) direction was observed. Cine-MRI using T(2)-weighted single shot fast spin echo sequences were acquired in three orthogonal planes during free breathing through the centroid of the most dominant liver tumor. ImageJ software was used to measure the maximal motion of the tumor edges in each plane. The intra- and interobserver reproducibility was also quantified. The average CC motion of the liver at fluoroscopy was 15 mm (range, 5-41). On cine-MRI, the average CC tumor motion was 15.5 mm (range, 6.9-35.4), the anteroposterior motion was 10 mm (range, 3.7-21.6), and the mediolateral motion was 7.5 mm (range, 3.8-14.8). The fluoroscopic CC diaphragm motion did not correlate well with the MRI CC tumor motion (r = 0.25). The mean intraobserver error was <2 mm in the CC, anteroposterior, and mediolateral directions, and 90% of measurements between observers were within 3 mm. The results of our study have shown that cine-MRI can be used to directly assess liver tumor motion in three dimensions. Tumor motion did not correlate well with the diaphragm motion measured using kilovoltage fluoroscopy. The tumor motion data from cine-MRI can be used to facilitate individualized planning target volume margins to account for breathing motion.

  20. Polyethylenimine-coated SPION exhibits potential intrinsic anti-metastatic properties inhibiting migration and invasion of pancreatic tumor cells.

    PubMed

    Mulens-Arias, Vladimir; Rojas, José Manuel; Pérez-Yagüe, Sonia; Morales, María del Puerto; Barber, Domingo F

    2015-10-28

    Due to its aggressive behavior, pancreatic cancer is one of the principal causes of cancer-related deaths. The highly metastatic potential of pancreatic tumor cells demands the development of more effective anti-metastatic approaches for this disease. Although polyethylenimine-coated superparamagnetic iron oxide nanoparticles (PEI-coated SPIONs) have been studied for their utility as transfection agents, little is known of their effect on tumor cell biology. Here we demonstrated that PEI-coated SPIONs have potent inhibitory effects on pancreatic tumor cell migration/invasion, through inhibition of Src kinase and decreased expression of MT1-MMP and MMP2 metalloproteinases. When treated with PEI-coated SPIONs, the pancreatic tumor cell line Pan02 showed reduced invadosome density and thus, a decrease in their ability to invade through basement membrane. These nanoparticles temporarily downmodulated microRNA-21, thereby upregulating the cell migration inhibitors PTEN, PDCD4 and Sprouty-1. PEI-coated SPIONs thus show intrinsic, possibly anti-metastatic properties for modulating pancreatic tumor cell migration machinery, which indicates their potential as anti-metastatic agents for treatment of pancreatic cancer.

  1. Incidence and Oncological Implications of Previously Undetected Tumor Multicentricity Following Pancreaticoduodenectomy for Pancreatic Adenocarcinoma in Patients Undergoing Salvage Pancreatectomy.

    PubMed

    Andreou, Andreas; Klein, Fritz; Schmuck, Rosa B; Lee, Daniela; Sinn, Marianne; Denecke, Timm; Pratschke, Johann; Bahra, Marcus

    2017-09-01

    The risk for multicentricity of pancreatic adenocarcinoma remains unclear and the question whether pancreaticoduodenectomy represents sufficient oncological treatment for patients with ductal adenocarcinoma of the head of the pancreas needs further investigation. Clinicopathological data of patients who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma between 2005 and 2015 were assessed and the incidence of tumor multicentricity among patients who required salvage pancreatectomy within 90 postoperative days was evaluated. Pancreaticoduodenectomy was performed in 1,005 patients. Sixty-two patients (6%) suffered a major postoperative complication (pancreatic fistula/anastomotic leak/bleeding) after resection of the head of the pancreas, requiring salvage pancreatectomy. Histological examination of the pancreatic remnant in patients with ductal adenocarcinoma (n=19) revealed multicentric carcinoma in two patients, resulting in an incidence of 11% for tumor multicentricity. Preoperative cross-sectional imaging failed to identify tumor multicentricity in these patients. Additionally, two patients with pancreatic intraepithelial neoplasia and two with neuroendocrine tumor were identified. The incidence of previously undetected multicentric adenocarcinoma among patients undergoing salvage pancreatectomy in our study was surprisingly high. This finding suggests that the role of total pancreatectomy for pancreatic head cancer, as well as the current strategies for postoperative tumor surveillance, should be re-evaluated in order to provide the best oncological approach and prolonged survival for patients with ductal adenocarcinoma. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells.

    PubMed

    Ting, David T; Wittner, Ben S; Ligorio, Matteo; Vincent Jordan, Nicole; Shah, Ajay M; Miyamoto, David T; Aceto, Nicola; Bersani, Francesca; Brannigan, Brian W; Xega, Kristina; Ciciliano, Jordan C; Zhu, Huili; MacKenzie, Olivia C; Trautwein, Julie; Arora, Kshitij S; Shahid, Mohammad; Ellis, Haley L; Qu, Na; Bardeesy, Nabeel; Rivera, Miguel N; Deshpande, Vikram; Ferrone, Cristina R; Kapur, Ravi; Ramaswamy, Sridhar; Shioda, Toshi; Toner, Mehmet; Maheswaran, Shyamala; Haber, Daniel A

    2014-09-25

    Circulating tumor cells (CTCs) are shed from primary tumors into the bloodstream, mediating the hematogenous spread of cancer to distant organs. To define their composition, we compared genome-wide expression profiles of CTCs with matched primary tumors in a mouse model of pancreatic cancer, isolating individual CTCs using epitope-independent microfluidic capture, followed by single-cell RNA sequencing. CTCs clustered separately from primary tumors and tumor-derived cell lines, showing low-proliferative signatures, enrichment for the stem-cell-associated gene Aldh1a2, biphenotypic expression of epithelial and mesenchymal markers, and expression of Igfbp5, a gene transcript enriched at the epithelial-stromal interface. Mouse as well as human pancreatic CTCs exhibit a very high expression of stromal-derived extracellular matrix (ECM) proteins, including SPARC, whose knockdown in cancer cells suppresses cell migration and invasiveness. The aberrant expression by CTCs of stromal ECM genes points to their contribution of microenvironmental signals for the spread of cancer to distant organs. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Metastatic pancreatic polypeptide-secreting islet cell tumor in a dog.

    PubMed

    Cruz Cardona, Janice A; Wamsley, Heather L; Farina, Lisa L; Kiupel, Matti

    2010-09-01

    A 14-year-old female spayed Golden Retriever was presented to the University of Florida's Veterinary Medical Center with history of lymphoplasmacytic gastroenteritis, intermittent vomiting, watery diarrhea, and weight loss for over a year. CBC, biochemical profile, and urinalysis were within reference intervals. Abdominal ultrasonographic examination revealed mesenteric and jejunal lymphadenopathy and hyperechoic hepatic nodules. Cytologic examination of the enlarged lymph nodes revealed loosely cohesive cells with moderate nuclear pleomorphism and rare punctate eosinophilic cytoplasmic granules. The cytologic interpretation was metastatic neuroendocrine neoplasia. On surgical exploration, a mass was detected in the right lobe of the pancreas. Histologic evaluation determined the mass to be an islet cell tumor. Approximately 98% of cells were positive by immunolabeling for pancreatic polypeptide (PP), and only rare cells were positive for insulin or somatostatin. All cells were negative for glucagon, gastrin, vasoactive intestinal polypeptide, protein gene product 9.5, synaptophysin, and chromogranins A and B. Pancreatic tumors that primarily produce PP are rare in dogs, and this is the first report of both the cytologic and histologic features of an islet cell tumor predominantly secreting PP. Clinical signs for these tumors are typically absent or nonspecific; signs may include watery diarrhea, as noted in this dog, although the diarrhea may have resulted from lymphoplasmacytic gastroenteritis. Additional case studies are needed to further characterize the cytomorphologic features and clinical presentation of PP-secreting islet cell tumor, or polypeptidoma, in dogs.

  4. A case of pancreatic neuroendocrine tumor in a patient with neurofibromatosis-1

    PubMed Central

    2012-01-01

    Patients with neurofibromatosis-1 (NF-1) sometime develop neuroendocrine tumors (NET). Although these NETs usually occur in the duodenum or peri-ampullary region, they occasionally grow in the pancreas (PNET). A 62-year-old man with NF-1 had mild liver dysfunction and was admitted to our hospital for further examination. An abdominal contrast-enhanced computed tomography scan demonstrated a 30-mm tumor in the head of the pancreas. The scan showed an invasion of the tumor into the duodenum, and biopsy under an endoscopic ultrasonography indicated that the tumor was a NET. A subtotal stomach-preserving pancreaticoduodenectomy was performed. Macroscopically, the pancreatic tumor was white and elastic hard. Microscopically, tumor cells were composed of ribbons, cords, and solid nests with an acinus-like structure. The tumor was diagnosed as NET G2 according to the WHO classification (2010). The product of theNF-1 gene, i.e., neurofibromin, was weakly positive in the tumor cells, suggesting that the tumor was induced by a mutation in the NF-1 gene. This is the seventh case of PNET arising in NF-1 patients worldwide. PMID:22824559

  5. Use of cinacalcet and sunitinib to treat hypercalcaemia due to a pancreatic neuroendocrine tumor.

    PubMed

    Valdes-Socin, Hernan; Almanza, Matilde Rubio; Fernández-Ladreda, Mariana Tomé; Daele, Daniel Van; Polus, Marc; Chavez, Marcela; Beckers, Albert

    2017-09-18

    Neuroendocrine tumors (NETs) can secrete hormones, including ectopic secretions, but they have been rarely associated with malignant hypercalcemia. A 52-year-old man with a history of diabetes mellitus was diagnosed with a pancreatic tumor. A pancreatic biopsy confirmed a well-differentiated pancreatic NET (pNET). The patient subsequently developed liver metastasis and hypercalcemia with high 1,25 OH vitamin D and suppressed parathyroid hormone (PTH) levels. Hypercalcemia was refractory to chemotherapy, intravenous saline fluids, diuretics, calcitonin and zoledronate. Cinacalcet administration (120 mg/day) resulted in a significant calcium reduction. Hypocalcemia was observed when sunitinib was added three months later and cinacalcet was stopped. Subsequently, the calcium and PTH levels normalized. After six months, we observed 20% shrinkage of the pancreatic tumor and necrosis of a liver metastasis. Cinacalcet is an allosteric activator of the calcium receptor agonist, and it is used for severe hypercalcemia in patients with primary (benign and malignant) hyperparathyroidism. In this patient, cinacalcet demonstrated a calcium lowering effect, normalized hypophosphatemia, and improved the clinical condition of the patient. The mechanism through which cinacalcet improved PTH-rp mediated hypercalcemia is still unclear, but studies have suggested that a potential mechanism is the activation of calcitonin secretion. Sunitinib is an oral multi-targeted tyrosine kinase inhibitor used to treat advanced pNETs. The hypocalcemic effects of sunitinib have not been previously described in a patient with pNET. Here, we report for the first time the successful combination of cinacalcet and sunitinib in the treatment of a pNET patient presenting with malignant hypercalcemia.

  6. COMPARING THE ENZYME REPLACEMENT THERAPY COST IN POST PANCREATECTOMY PATIENTS DUE TO PANCREATIC TUMOR AND CHRONIC PANCREATITIS.

    PubMed

    Fragoso, Anna Victoria; Pedroso, Martha Regina; Herman, Paulo; Montagnini, André Luis

    2016-01-01

    Among late postoperative complications of pancreatectomy are the exocrine and endocrine pancreatic insufficiencies. The presence of exocrine pancreatic insufficiency imposes, as standard treatment, pancreatic enzyme replacement. Patients with chronic pancreatitis, with intractable pain or any complications with surgical treatment, are likely to present exocrine pancreatic insufficiency or have this condition worsened requiring adequate dose of pancreatic enzymes. The aim of this study is to compare the required dose of pancreatic enzyme and the enzyme replacement cost in post pancreatectomy patients with and without chronic pancreatitis. Observational cross-sectional study. In the first half of 2015 patients treated at the clinic of the Department of Gastrointestinal Surgery at Hospital das Clínicas, Universidade de São Paulo, Brazil, who underwent pancreatectomy for at least 6 months and in use of enzyme replacement therapy were included in this series. The study was approved by the Research Ethics Committee. The patients were divided into two groups according to the presence or absence of chronic pancreatitis prior to pancreatic surgery. For this study, P<0.05 was considered statistically significant. The annual cost of the treatment was R$ 2150.5 ± 729.39; R$ 2118.18 ± 731.02 in patients without pancreatitis and R$ 2217.74 ± 736.30 in patients with pancreatitis. There was no statistically significant difference in the cost of treatment of enzyme replacement post pancreatectomy in patients with or without chronic pancreatitis prior to surgical indication.

  7. Pancreatic ductal adenocarcinoma mice lacking mucin 1 have a profound defect in tumor growth and metastasis.

    PubMed

    Besmer, Dahlia M; Curry, Jennifer M; Roy, Lopamudra D; Tinder, Teresa L; Sahraei, Mahnaz; Schettini, Jorge; Hwang, Sun-Il; Lee, Yong Y; Gendler, Sandra J; Mukherjee, Pinku

    2011-07-01

    MUC1 is overexpressed and aberrantly glycosylated in more than 60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In this study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared with both KC and KCM. Cell lines derived from KCKO tumors have significantly less tumorigenic capacity compared with cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared with mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor, platelet-derived growth factor, or matrix metalloproteinase 9. Further, significantly less KCKO cells entered the G(2)-M phase of the cell cycle compared with the KCM cells. Proteomics and Western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of mitogen-activated protein kinase (MAPK), as well as a significant decrease in nestin and tubulin-α2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. ©2011 AACR

  8. Assessment of biophysical tumor response to PDT in pancreatic cancer using localized reflectance spectroscopy

    NASA Astrophysics Data System (ADS)

    Isabelle, Martin; Klubben, William; He, Ting; Laughney, Ashley M.; Glaser, Adam; Krishnaswamy, Venkataramanan; Hoopes, P. Jack; Hasan, Tayyaba; Pogue, Brian W.

    2011-02-01

    Biophysical changes such as inflammation and necrosis occur immediately following PDT and may be used to assess the treatment response to PDT treatment in-vivo. This study uses localized reflectance measurements to quantify the scatter changes in tumor tissue occurring in response to verteporfin-based PDT treatment in xenograft pancreas tumors. Nude mice were implanted with subcutaneous AsPC-1 pancreatic tumors cells in matrigel, and allowed to establish solid tumors near 100mm3 volume. The mice were sensitized with 1mg/kg of the active component of verteporfin (benzoporphryin derivative, BPD), one hour before light delivery. The optical irradiation was performed using a 1 cm cylindrical interstitial diffusing tip fiber with 20J of red light (690nm). Tumor tissue was excised progressively and imaged, from 1 day to 4 weeks, after PDT treatment. The tissue sections were stained and analyzed by an expert veterinary pathologist, who provided information on tissue regions of interest. This information was correlated with variations in scattering and absorption parameters elucidated from the spectral images and the degree of necrosis and inflammation involvement was identified. Areas of necrosis and dead cells exhibited the lowest average scatter irradiance signature (3.78 and 4.07 respectively) compared to areas of viable pancreatic tumor cells and areas of inflammation (5.81 and 7.19 respectively). Bilirubin absorbance parameters also showed a lower absorbance value in necrotic tissue and areas of dead cells (0.05 and 0.1 respectively) compared to tissue areas for viable pancreatic tumor cells and areas of inflammation (0.28 and 0.35). These results demonstrate that localized reflectance spectroscopy is an imaging modality that can be used to identify tissue features associated with PDT treatment (e.g. necrosis and inflammation) that can be correlated with histopathologically-reviewed H&E stained slides. Further study of this technique may provide means for automated

  9. Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma

    PubMed Central

    Huang, Peng; Wang, Chun-You; Gou, Shan-Miao; Wu, He-Shui; Liu, Tao; Xiong, Jiang-Xin

    2008-01-01

    AIM: To explore the method of isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma cell line PANC-1. METHODS: The PANC-1 cells were cultured in Dulbecco modified eagle medium F12 (1:1 volume) (DMEM-F12) supplemented with 20% fetal bovine serum (FBS). Subpopulation cells with properties of tumor stem cells were isolated from pancreatic adenocarcinoma cell line PANC-1 according to the cell surface markers CD44 and CD24 by flow cytometry. The proliferative capability of these cells in vitro were estimated by 3-[4,5-dimehyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide (MTT) method. And the tumor growth of different subpopulation cells which were injected into the hypodermisof right and left armpit of nude mice was studied, and expression of CD44 and CD24 of the CD44+CD24+ cell-formed nodules and PANC-1 cells were detected by avidin-biotin-peroxidase complex (ABC) immunohistochemical staining. RESULTS: The 5.1%-17.5% of sorted PANC-1 cells expressed the cell surface marker CD44, 57.8% -70.1% expressed CD24, only 2.1%-3.5% of cells were CD44+ CD24+. Compared with CD44-CD24- cells, CD44+CD24+ cells had a lower growth rate in vitro. Implantation of 104 CD44-CD24- cells in nude mice showed no evident tumor growth at wk 12. In contrast, large tumors were found in nude mice implanted with 103 CD44+CD24+ cells at wk 4 (2/8), a 20-fold increase in tumorigenic potential (P < 0.05 or P < 0.01). There was no obvious histological difference between the cells of the CD44+CD24+ cell-formed nodules and PANC-1 cells. CONCLUSION: CD44 and CD24 may be used as the cell surface markers for isolation of pancreatic cancer stem cells from pancreatic adenocarcinoma cell line PANC-1. Subpopulation cells CD44+CD24+ have properties of tumor stem cells. Because cancer stem cells are thought to be responsible for tumor initiation and its recurrence after an initial response to chemotherapy, it may be a very promising target for new drug development. PMID

  10. Orchestrating the Tumor Microenvironment to Improve Survival for Patients With Pancreatic Cancer Normalization, Not Destruction

    PubMed Central

    Whatcott, Clifford J.; Hanl, Haiyong; Von Hoff, Daniel D.

    2016-01-01

    Pancreatic cancer is the fourth leading cause of cancer death in the United States. The microenvironment of pancreatic cancer could be one of the “perfect storms” that support the growth of a cancer. Indeed, pancreatic cancer may be the poster child of a problem with the microenvironment. In this article, we review the rationale and attempts to date on modifying or targeting structural proteins in the microenvironment including hyaluronan (HA) (in primary and metastases), collagen, and SPARC (secreted protein, acidic, and rich in cysteine). Indeed, working in this area has produced a regimen that improves survival for patients with advanced pancreatic cancer (nab-paclitaxel + gemcitabine). In addition, in initial clinical trials, PEGylated hyaluronidase appears promising. We also review a new approach that is different than targeting/destroying the microenvironment and that is orchestrating, reengineering, reprogramming, or normalizing the microenvironment (including normalizing structural proteins, normalizing an immunologically tumor-friendly environment to a less friendly environment, reversing epithelial-to-mesenchymal transition, and so on). We believe this will be most effectively done by agents that have global effects on transcription. There is initial evidence that this can be done by agents such as vitamin D derivatives and other new agents. There is no doubt these opportunities can now be tried in the clinic with hopefully beneficial effects. PMID:26222082

  11. Portal vein-circulating tumor cells predict liver metastases in patients with resectable pancreatic cancer.

    PubMed

    Bissolati, Massimiliano; Sandri, Maria Teresa; Burtulo, Giovanni; Zorzino, Laura; Balzano, Gianpaolo; Braga, Marco

    2015-02-01

    Pancreatic cancer patients underwent surgical resection often present distant metastases early after surgery. Detection of circulating tumor cells (CTCs) has been correlated to a worse oncological outcome in patients with advanced pancreatic cancer. The objective of this pilot study is to investigate the possible prognostic role of CTCs in patients undergoing surgery for pancreatic cancer. In 20 patients undergoing pancreatic resection, 10 mL blood sample was collected intraoperatively from both systemic circulation (SC) and portal vein (PV). Blood sample was analyzed for CTCs with CellSearch® system. All patients underwent an oncologic follow-up for at least 3 years, quarterly. CTCs were detected in nine (45%) patients: five patients had CTCs in PV only, three patients in both SC and PV, and one patient in SC only. CTC-positive and CTC-negative patients were similar for demographics and cancer stage pattern. No significant differences were found in both overall and disease-free survival between CTC-positive and CTC-negative patients. At 3-year follow-up, portal vein CTC-positive patients presented a higher rate of liver metastases than CTC-negative patients (53 vs. 8%, p = 0.038). CTCs were found in 45% of the patients. No correlation between CTCs and survival was found. The presence of CTCs in portal vein has been associated to higher rate of liver metastases after surgery.

  12. Zyflamend Suppresses Growth and Sensitizes Human Pancreatic Tumors to Gemcitabine in an Orthotopic Mouse Model Through Modulation of Multiple Targets

    PubMed Central

    Kunnumakkara, Ajaikumar B.; Sung, Bokyung; Ravindran, Jayaraj; Diagaradjane, Parmeswaran; Deorukhkar, Amit; Dey, Sanjit; Koca, Cemile; Tong, Zhimin; Gelovani, Juri G.; Guha, Sushovan; Krishnan, Sunil; Aggarwal, Bharat B.

    2011-01-01

    Agents that can potentiate the efficacy of standard chemotherapy against pancreatic cancer are of great interest. Because of their low cost and safety, patients commonly use a variety of dietary supplements, although evidence of their efficacy is often lacking. One such commonly used food supplement, Zyflamend, is a polyherbal preparation with potent anti-inflammatory activities, and preclinical efficacy against prostate and oral cancer. Whether Zyflamend has any efficacy against human pancreatic cancer alone or in combination with gemcitibine, a commonly used agent, was examined in cell cultures and in an orthotopic mouse model. In vitro, Zyflamend inhibited the proliferation of pancreatic cancer cell lines regardless of p53 status and also enhanced gemcitabine-induced apoptosis. This finding correlated with inhibition of NF-κB activation by Zyflamend and suppression of cyclin D1, c-myc, COX-2, Bcl-2, IAP, survivin, VEGF, ICAM-1, and CXCR4. In nude mice, oral administration of Zyflamend alone significantly inhibited the growth of orthotopically transplanted human pancreatic tumors, and when combined with gemcitabine, further enhanced the antitumor effects. Immunohistochemical and Western blot analyses of tumor tissue showed that the suppression of pancreatic cancer growth correlated with inhibition of proliferation index marker (Ki-67), COX-2, MMP-9, NF-κB, and VEGF. Overall, these results suggest that the concentrated multiherb product Zyflamend alone can inhibit the growth of human pancreatic tumors and, in addition, can sensitize pancreatic cancers to gemcitabine through the suppression of multiple targets linked to tumorigenesis. PMID:21935918

  13. Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle.

    PubMed

    Ernsting, Mark J; Hoang, Bryan; Lohse, Ines; Undzys, Elijus; Cao, Pinjiang; Do, Trevor; Gill, Bethany; Pintilie, Melania; Hedley, David; Li, Shyh-Dar

    2015-05-28

    Pancreatic ductal adenocarcinomas are characterized by the desmoplastic reaction, a dense fibrous stroma that has been shown to be supportive of tumor cell growth, invasion, and metastasis, and has been associated with resistance to chemotherapy and reduced patient survival. Here, we investigated targeted depletion of stroma for pancreatic cancer therapy via taxane nanoparticles. Cellax-DTX polymer is a conjugate of docetaxel (DTX), polyethylene glycol (PEG), and acetylated carboxymethylcellulose, a construct which condenses into well-defined 120nm particles in an aqueous solution, and is suitable for intravenous injection. We examined Cellax-DTX treatment effects in highly stromal primary patient-derived pancreatic cancer xenografts and in a metastatic PAN02 mouse model of pancreatic cancer, focusing on specific cellular interactions in the stroma, pancreatic tumor growth and metastasis. Greater than 90% of Cellax-DTX particles accumulate in smooth muscle actin (SMA) positive cancer-associated fibroblasts which results in long-term depletion of this stromal cell population, an effect not observed with Nab-paclitaxel (Nab-PTX). The reduction in stromal density leads to a >10-fold increase in tumor perfusion, reduced tumor weight and a reduction in metastasis. Consentingly, Cellax-DTX treatment increased survival when compared to treatment with gemcitabine or Nab-PTX in a metastatic PAN02 mouse model. Cellax-DTX nanoparticles interact with the tumor-associated stroma, selectively interacting with and depleting SMA positive cells and macrophage, effects of which are associated with significant changes in tumor progression and metastasis.

  14. 99mTc-HYNIC-TOC imaging in the evaluation of pancreatic masses which are potential neuroendocrine tumors.

    PubMed

    Qiao, Zhen; Zhang, Jingjing; Jin, Xiaona; Huo, Li; Zhu, Zhaohui; Xing, Haiqun; Li, Fang

    2015-05-01

    The aim of this investigation was to determine the accuracy of the findings and the diagnoses of Tc-hydrazinonicotinyl-Tyr3-octreotide scan (Tc-HYNIC-TOC imaging) in patients with pancreatic masses which were potential neuroendocrine tumors. Records of total 20 patients with pancreatic masses were retrospectively reviewed. All of the patients had been revealed by abdominal contrast CT and possibility of neuroendocrine tumors could not be excluded by CT imaging before Tc-HYNIC-TOC imaging. Tc-HYNIC-TOC imaging was performed at 1 and 4 hours post-tracer injection, and SPECT/CT images of the abdomen were also acquired. The image findings were compared to final diagnoses which were made from pathological examination. Among all 20 pancreatic masses evaluated, there were 16 malignant lesions which included 1 ductal adenocarcinoma and 15 neuroendocrine tumors. Tc-HYNIC-TOC imaging identified 14 of 15 pancreatic neuroendocrine tumors and excluded 4 of 5 lesions which were not neuroendocrine tumors. The overall sensitivity, specificity, and accuracy was therefore 93.3% (14 of 15), 80% (4 of 5), and 90.0% (18 of 20), respectively, in our patient population. Tc-HYNIC-TOC imaging provides reasonable accuracy in the evaluation pancreatic mass suspected to be neuroendocrine tumors.

  15. Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay.

    PubMed

    Schneiderhan, Wilhelm; Diaz, Fredy; Fundel, Martin; Zhou, Shaoxia; Siech, Marco; Hasel, Cornelia; Möller, Peter; Gschwend, Jürgen E; Seufferlein, Thomas; Gress, Thomas; Adler, Guido; Bachem, Max G

    2007-02-01

    The effect of the characteristic desmoplastic reaction of pancreatic cancer on tumor progression is largely unknown. We investigated whether pancreatic stellate cells, which are responsible for the desmoplastic reaction, support tumor progression. Immunohistology revealed that matrix metalloproteinase-2 (MMP-2), which is suggested to promote pancreatic cancer progression, is present in stellate cells adjacent to cancer cells. In vitro, stellate cells exhibited a much higher basal expression of MMP-2 compared with cancer cells. Panc1-, MiaPaCa2- and SW850-conditioned media stimulated MMP-2 release of stellate cells as detected by zymography. Cancer cells expressed and released basigin [BSG, extracellular matrix metalloproteinase inducer (EMMPRIN), CD147], a glycoprotein that is known to stimulate MMP-2 in mesenchymal cells, as detected by immunostaining, western blot and reverse transcription-polymerase chain reaction. Tumor cell-conditioned medium and BSG purified by affinity chromatography from supernatants of cancer cells, but not supernatants depleted from BSG, stimulated expression of MMP-1 and MMP-2 of stellate cells as demonstrated by western blot and zymography. Moreover, the interaction of stellate cells and cancer cells promoted the invasiveness of Panc-1 cells in the chorioallantoic membrane assay and increased the weight of tumors induced by all carcinoma cell lines in nude mice by 2.1-3.7-fold. Our findings support the assumption that the interaction of stellate cells and cancer cells promotes progression of pancreatic cancer.

  16. Pancreatic tumor cell metabolism: focus on glycolysis and its connected metabolic pathways.

    PubMed

    Guillaumond, Fabienne; Iovanna, Juan Lucio; Vasseur, Sophie

    2014-03-01

    Because of lack of effective treatment, pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of death by cancer in Western countries, with a very weak improvement of survival rate over the last 40years. Defeat of numerous conventional therapies to cure this cancer makes urgent to develop new tools usable by clinicians for a better management of the disease. Aggressiveness of pancreatic cancer relies on its own hallmarks: a low vascular network as well as a prominent stromal compartment (desmoplasia), which creates a severe hypoxic environment impeding correct oxygen and nutrients diffusion to the tumoral cells. To survive and proliferate in those conditions, pancreatic cancer cells set up specific metabolic pathways to meet their tremendous energetic and biomass demands. However, as PDAC is a heterogenous tumor, a complex reprogramming of metabolic processes is engaged by cancer cells according to their level of oxygenation and nutrients supply. In this review, we focus on the glycolytic activity of PDAC and the glucose-connected metabolic pathways which contribute to the progression and dissemination of this disease. We also discuss possible therapeutic strategies targeting these pathways in order to cure this disease which still until now is resistant to numerous conventional treatments.

  17. Portal Venous Blood Circulation Supports Immunosuppressive Environment and Pancreatic Cancer Circulating Tumor Cell Activation.

    PubMed

    Arnoletti, Juan Pablo; Zhu, Xiang; Almodovar, Alvin J O; Veldhuis, Paula P; Sause, Ryan; Griffith, Elizabeth; Corpus, George; Chang, Jeffrey C C; Fanaian, Naʼim; Litherland, Sally A

    2017-01-01

    Aggressive spread and liver metastases are predominant features of pancreatic ductal adenocarcinoma (PDAC). This study investigates activation of PDAC circulating tumor cells (CTC) and immunosuppression in the portal venous system. Portal venous and peripheral blood were collected during pancreaticoduodenectomy from patients with PDAC (n = 21) or other non-PDAC pancreatic conditions (n = 20). Circulating tumor cells were isolated by fluorescence-activated cell sorting and characterized for messenger RNA (mRNA) expression and acetylated chromatin encoding K-RAS exon 12 mutation (K-RASmut). Myeloid-derived suppressor cells (MDSC) were identified using flow cytometry. Pancreatic ductal adenocarcinoma K-RASmut mRNA expression in portal venous blood CTC was significantly elevated compared with preoperative and postoperative peripheral blood (P = 0.0123 and P = 0.0246, respectively). There was no significant variation in total CTC numbers between portal and peripheral blood.Portal venous M-MDSC were elevated compared with peripheral blood in PDAC patients (P = 0.0065). M-MDSC increases correlated with K-RASmut mRNA-expressing CTC present in PDAC portal blood (P < 0.0001). Association of MDSC with active CTC in portal venous blood may support immunosuppression within the portal venous circulation to promote PDAC CTC survival.

  18. Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice

    PubMed Central

    Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George

    2016-01-01

    Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs

  19. Tumor Microenvironment Modulation by Cyclopamine Improved Photothermal Therapy of Biomimetic Gold Nanorods for Pancreatic Ductal Adenocarcinomas.

    PubMed

    Jiang, Ting; Zhang, Bo; Shen, Shun; Tuo, Yanyan; Luo, Zimiao; Hu, Yu; Pang, Zhiqing; Jiang, Xinguo

    2017-09-20

    Due to the rich stroma content and poor blood perfusion, pancreatic ductal adenocarcinoma (PDA) is a tough cancer that can hardly be effectively treated by chemotherapeutic drugs. Tumor microenvironment modulation or advanced design of nanomedicine to achieve better therapeutic benefits for PDA treatment was widely advocated by many reviews. In the present study, a new photothermal therapy strategy of PDA was developed by combination of tumor microenvironment modulation and advanced design of biomimetic gold nanorods. On one hand, biomimetic gold nanorods were developed by coating gold nanorods (GNRs) with erythrocyte membrane (MGNRs). It was shown that MGNRs exhibited significantly higher colloidal stability in vitro, stronger photothermal therapeutic efficacy in vitro, and longer circulation in vivo than GNRs. On the other hand, tumor microenvironment modulation by cyclopamine treatment successfully disrupted the extracellular matrix of PDA and improved tumor blood perfusion. Moreover, cyclopamine treatment significantly increased the accumulation of MGNRs in tumors by 1.8-fold and therefore produced higher photothermal efficiency in vivo than the control group. Finally, cyclopamine treatment combined with photothermal MGNRs achieved the most significant shrinkage of Capan-2 tumor xenografts among all the treatment groups. Therefore, with the integrated advantages of tumor microenvironment regulation and long-circulation biomimetic MGNRs, effective photothermal therapy of PDA was achieved. In general, this new strategy of combining tumor microenvironment modulation and advanced design of biomimetic nanoparticles might have great potential in PDA therapy.

  20. Unusual association of alveolar rhabdomyosarcoma with pancreatic metastasis: emerging role of PET-CT in tumor staging

    PubMed Central

    Jha, Priyanka; Frölich, Andreas M. J.; McCarville, Beth; Navarro, Oscar M.; Babyn, Paul; Goldsby, Robert

    2010-01-01

    Background Pancreatic metastases in childhood cancer have been rarely reported in the radiology literature although ample evidence exists in pathology reports for its occurrence in patients with alveolar rhabdomyosarcomas (RMS). Objective Assess the occurrence of pancreatic metastases in alveolar rhabdomyosarcomas, increase awareness of this association and reassess current staging protocols. Materials and methods Three major oncology centers reviewed their records and imaging examinations. Patients’ history and demographics, primary tumor site and histology, presence of tumor recurrence, and presence and location of other metastases were reviewed. Results Pancreatic metastases occurred in eight patients with alveolar RMS. Four of these presented at diagnosis and four with disease recurrence. In recurrent disease, the duration between the diagnosis of the primary tumor and pancreatic metastases varied from 8 months to 6 years (mean ± SD: 2.38 ± 2.49 years). In all patients who received PET scans, pancreatic metastases showed a marked FDG-uptake, but had variable detectability with CT. Pancreatic metastases were not associated with certain primary tumor locations or presence of other metastases, mandating an evaluation of the pancreas in all cases of alveolar rhabdomyosarcomas. Conclusion Radiologists should be sensitized and actively evaluate the pancreas in patients with alveolar RMS. Optimizing CT and PET-CT protocols may increase the diagnostic yield. PMID:20180103

  1. Comprehensive treatment of a functional pancreatic neuroendocrine tumor with multifocal liver metastases

    PubMed Central

    Wang, Wei; Seeruttun, Sharvesh Raj; Fang, Cheng

    2014-01-01

    A 64-year-old man was admitted to the Sun Yat-Sen University Cancer Center with chief complaints of recurrent abdominal pain and diarrhea for about 3 years and with a history of surgical repair for intestinal perforation owing to stress ulcer. Positron emission tomography (PET)/computed tomography (CT) demonstrated a primary tumor on the pancreatic tail with multifocal liver metastases. Pathological and immunohistochemistry staining revealed the lesion to be a pancreatic neuroendocrine tumor (pNET). According to the latest World Health Organization (WHO, 2013) classification, the tumor was classified as stage IV functional G1 pNET. After referral to the multidisciplinary treatment board (MDT), the patient was started on periodic dose of omeprazole, somatostatin analogues and Interferon α (IFNα) and had scanning follow-ups. Based upon the imaging results, CT-guided radioactive iodine-125 (125I) seeds implantation therapy, radiofrequency ablation therapy (RFA) or microwave ablation technique were chosen for the treatment of the primary tumor. Transarterial chemoembolization (TACE), RFA and microwave ablation techniques were decided upon for liver metastases. The patient showed beneficial response to the treatment with clinically manageable low-grade side effects and attained partial remission (RECIST criteria) with a good quality of life. PMID:25232226

  2. Comprehensive treatment of a functional pancreatic neuroendocrine tumor with multifocal liver metastases.

    PubMed

    Wang, Wei; Seeruttun, Sharvesh Raj; Fang, Cheng; Zhou, Zhiwei

    2014-08-01

    A 64-year-old man was admitted to the Sun Yat-Sen University Cancer Center with chief complaints of recurrent abdominal pain and diarrhea for about 3 years and with a history of surgical repair for intestinal perforation owing to stress ulcer. Positron emission tomography (PET)/computed tomography (CT) demonstrated a primary tumor on the pancreatic tail with multifocal liver metastases. Pathological and immunohistochemistry staining revealed the lesion to be a pancreatic neuroendocrine tumor (pNET). According to the latest World Health Organization (WHO, 2013) classification, the tumor was classified as stage IV functional G1 pNET. After referral to the multidisciplinary treatment board (MDT), the patient was started on periodic dose of omeprazole, somatostatin analogues and Interferon α (IFNα) and had scanning follow-ups. Based upon the imaging results, CT-guided radioactive iodine-125 ((125)I) seeds implantation therapy, radiofrequency ablation therapy (RFA) or microwave ablation technique were chosen for the treatment of the primary tumor. Transarterial chemoembolization (TACE), RFA and microwave ablation techniques were decided upon for liver metastases. The patient showed beneficial response to the treatment with clinically manageable low-grade side effects and attained partial remission (RECIST criteria) with a good quality of life.

  3. Neuroendocrine tumor targeting: study of novel gallium-labeled somatostatin radiopeptides in a rat pancreatic tumor model.

    PubMed

    Froidevaux, Sylvie; Eberle, Alex N; Christe, Martine; Sumanovski, Lazar; Heppeler, Axel; Schmitt, Jörg S; Eisenwiener, Klaus; Beglinger, Christoph; Mäcke, Helmut R

    2002-04-20

    Somatostatin analogs labeled with radionuclides are of considerable interest in the diagnosis and therapy of SSTR-expressing tumors, such as gastroenteropancreatic, small cell lung, breast and frequently nervous system tumors. In view of the favorable physical characteristics of the Ga isotopes (67)Ga and (68)Ga, enabling conventional tumor scintigraphy, PET and possibly internal radiotherapy, we focused on the development of a Ga-labeled somatostatin analog suitable for targeting SSTR-expressing tumors. For this purpose, 3 somatostatin analogs, OC, TOC and TATE were conjugated to the metal chelator DOTA and labeled with the radiometals (111)In, (90)Y and (67)Ga. They were then evaluated for their performance in the AR4-2J pancreatic tumor model by testing SSTR2-binding affinity, internalization/externalization in isolated cells and biodistribution in tumor-bearing nude mice. Surprisingly, we found that, compared to (111)In or (90)Y, labeling with (67)Ga considerably improved the biologic performance of the tested somatostatin analogs with respect to SSTR2 affinity and tissue distribution. (67)Ga-labeled DOTA-somatostatin analogs were rapidly excreted from nontarget tissues, leading to excellent tumor-to-nontarget tissue uptake ratios. Of interest for radiotherapeutic application, [(67)Ga]DOTATOC was strongly internalized by AR4-2J cells. Furthermore, our results suggest a link between the radioligand charge and its kidney retention. The excellent tumor selectivity of Ga-DOTA somatostatin analogs together with the different applications of Ga in nuclear oncology suggests that Ga-DOTA somatostatin analogs will become an important tool in the management of SSTR-positive tumors. Copyright 2002 Wiley-Liss, Inc.

  4. APN401 in Treating Patients With Melanoma, Kidney Cancer, Pancreatic Cancer, or Other Solid Tumors That Are Metastatic or Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2017-08-14

    Recurrent Melanoma; Recurrent Pancreatic Cancer; Recurrent Renal Cell Cancer; Stage III Pancreatic Cancer; Stage III Renal Cell Cancer; Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma; Stage IV Pancreatic Cancer; Stage IV Renal Cell Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  5. “Stealth dissemination” of macrophage-tumor cell fusions cultured from blood of patients with pancreatic ductal adenocarcinoma

    USDA-ARS?s Scientific Manuscript database

    Circulating tumor cells (CTCs) appear to be involved in early dissemination of many cancers, although which characteristics are important in metastatic spread are not clear. Here we describe isolation and characterization of macrophage-tumor cell fusions (MTFs) from the blood of pancreatic ductal a...

  6. Thermal therapy of pancreatic tumors using endoluminal ultrasound: parametric and patient-specific modeling

    PubMed Central

    Adams, Matthew S.; Scott, Serena J.; Salgaonkar, Vasant A.; Sommer, Graham; Diederich, Chris J.

    2016-01-01

    Purpose To investigate endoluminal ultrasound applicator configurations for volumetric thermal ablation and hyperthermia of pancreatic tumors using 3D acoustic and biothermal finite element models. Materials and Methods Parametric studies compared endoluminal heating performance for varying applicator transducer configurations (planar, curvilinear-focused, or radial-diverging), frequencies (1–5 MHz), and anatomical conditions. Patient-specific pancreatic head and body tumor models were used to evaluate feasibility of generating hyperthermia and thermal ablation using an applicator positioned in the duodenal or stomach lumen. Temperature and thermal dose were calculated to define ablation (>240 EM43°C) and moderate hyperthermia (40–45 °C) boundaries, and to assess sparing of sensitive tissues. Proportional-integral control was incorporated to regulate maximum temperature to 70–80 °C for ablation and 45 °C for hyperthermia in target regions. Results Parametric studies indicated that 1–3 MHz planar transducers are most suitable for volumetric ablation, producing 5–8 cm3 lesion volumes for a stationary 5 minute sonication. Curvilinear-focused geometries produce more localized ablation to 20–45 mm depth from the GI tract and enhance thermal sparing (Tmax<42 °C) of the luminal wall. Patient anatomy simulations show feasibility in ablating 60.1–92.9% of head/body tumor volumes (4.3–37.2 cm3) with dose <15 EM43°C in the luminal wall for 18–48 min treatment durations, using 1–3 applicator placements in GI lumen. For hyperthermia, planar and radial-diverging transducers could maintain up to 8 cm3 and 15 cm3 of tissue, respectively, between 40–45 °C for a single applicator placement. Conclusions Modeling studies indicate the feasibility of endoluminal ultrasound for volumetric thermal ablation or hyperthermia treatment of pancreatic tumor tissue. PMID:27097663

  7. MicroRNAs Targeting Oncogenes Are Down-Regulated in Pancreatic Malignant Transformation from Benign Tumors

    PubMed Central

    Jiao, Long R.; Frampton, Adam E.; Jacob, Jimmy; Pellegrino, Loredana; Krell, Jonathan; Giamas, Georgios; Tsim, Nicole; Vlavianos, Panagiotis; Cohen, Patrizia; Ahmad, Raida; Keller, Andreas; Habib, Nagy A.; Stebbing, Justin; Castellano, Leandro

    2012-01-01

    Background MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. Methods Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. Results Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a “seedless” binding site within its 3′UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. Conclusions Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show

  8. Multiorgan chronic inflammatory hepatobiliary pancreatic murine model deficient in tumor necrosis factor receptors 1 and 2

    PubMed Central

    Oz, Helieh S

    2016-01-01

    AIM: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues. METHODS: Tumor necrosis factor receptors 1 and 2 (TNFR1/R2) deficient mice reared in-house were given dibutyltin dichloride (DBTC) twice within 10 d by oral gavage delivery. Sham control animals received vehicle treatment and naïve animals remained untreated throughout the study. Animals were monitored daily for symptoms of pain and discomfort. The abdominal and hindpaw hypersensitivity were assessed with von Frey microfilaments. Exploratory behaviors were recorded at the baseline, after initiation of treatment, and before study termination. Histopathological changes were examined postmortem in tissues. Collagen accumulation and fibrosis were confirmed with Sirius Red staining. RESULTS: Animals lost weight after oral administration of DBTC and developed persistent inflammatory abdominal and hindpaw hypersensitivity compared to sham-treated controls (P < 0.0001). These pain related secondary mechanical hypersensitivity responses increased more than 2-fold in DBTC-treated animals. The drastically diminished rearing and grooming rates persisted after DBTC administration throughout the study. Gross as well as micropathology at one month confirmed that animals treated with DBTC developed chronic hepatobiliary injuries evidenced with activation of stellate cells, multifocal necrosis, fatty degeneration of hepatocytes, periportal infiltration of inflammatory cells, and prominent biliary ductal dilation. The severity of hepatitis was scored 3.7 ± 0.2 (severe) in DBTC-treated animals vs score 0 (normal) in sham-treated animals. Fibrotic thickening was extensive around portal ducts, in hepatic parenchyma as well as in lobular pancreatic structures and confirmed with Sirius Red histopathology. In addition, pancreatic microarchitecture was presented with distortion of islets, and parenchyma, infiltration of

  9. Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression.

    PubMed

    Zhu, Yu; Herndon, John M; Sojka, Dorothy K; Kim, Ki-Wook; Knolhoff, Brett L; Zuo, Chong; Cullinan, Darren R; Luo, Jingqin; Bearden, Audrey R; Lavine, Kory J; Yokoyama, Wayne M; Hawkins, William G; Fields, Ryan C; Randolph, Gwendalyn J; DeNardo, David G

    2017-08-15

    Tumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originated from embryonic development and expanded through in situ proliferation during tumor progression. Whereas monocyte-derived TAMs played more potent roles in antigen presentation, embryonically derived TAMs exhibited a pro-fibrotic transcriptional profile, indicative of their role in producing and remodeling molecules in the extracellular matrix. Collectively, these findings uncover the heterogeneity of TAM origin and functions and could provide therapeutic insight for PDAC treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Iodine-123 MIBG imaging in a generalized pancreatic polypeptide-gastrin-serotonin secreting tumor

    SciTech Connect

    Somers, G.; Vanden Houte, K.; Segers, O.; Bossuyt, A.

    1988-05-01

    The usefulness of radio-metaiodobenzylguanidine (MIBG), a specific radiopharmaceutical agent for scintigraphic imaging and treatment of phaeochromocytoma and neuroblastoma, has been extended to the location of carcinoid tumors. Scintigraphic evaluation with I-123 MIBG in a patient with a histologically proven endocrine tumor (apudoma) of unknown origin with liver and bone metastases is reported. Elevated plasma hormone levels of gastrin, pancreatic polypeptide, and serotonin were found. Tumoral content of these hormones was immunocytochemically confirmed on liver biopsy. I-123 MIBG uptake could be seen in those areas of the liver with deficient lesions in the Tc-99m colloid image with a maximal uptake in a large mass at the level of the left liver lobe. No abnormal uptake could be observed at any other level, which was in contrast with autopsy findings of generalized metastatic disease.

  11. SU-E-J-29: Audiovisual Biofeedback Improves Tumor Motion Consistency for Lung Cancer Patients

    SciTech Connect

    Lee, D; Pollock, S; Makhija, K; Keall, P; Greer, P; Arm, J; Hunter, P; Kim, T

    2014-06-01

    Purpose: To investigate whether the breathing-guidance system: audiovisual (AV) biofeedback improves tumor motion consistency for lung cancer patients. This will minimize respiratory-induced tumor motion variations across cancer imaging and radiotherapy procedues. This is the first study to investigate the impact of respiratory guidance on tumor motion. Methods: Tumor motion consistency was investigated with five lung cancer patients (age: 55 to 64), who underwent a training session to get familiarized with AV biofeedback, followed by two MRI sessions across different dates (pre and mid treatment). During the training session in a CT room, two patient specific breathing patterns were obtained before (Breathing-Pattern-1) and after (Breathing-Pattern-2) training with AV biofeedback. In each MRI session, four MRI scans were performed to obtain 2D coronal and sagittal image datasets in free breathing (FB), and with AV biofeedback utilizing Breathing-Pattern-2. Image pixel values of 2D images after the normalization of 2D images per dataset and Gaussian filter per image were used to extract tumor motion using image pixel values. The tumor motion consistency of the superior-inferior (SI) direction was evaluated in terms of an average tumor motion range and period. Results: Audiovisual biofeedback improved tumor motion consistency by 60% (p value = 0.019) from 1.0±0.6 mm (FB) to 0.4±0.4 mm (AV) in SI motion range, and by 86% (p value < 0.001) from 0.7±0.6 s (FB) to 0.1±0.2 s (AV) in period. Conclusion: This study demonstrated that audiovisual biofeedback improves both breathing pattern and tumor motion consistency for lung cancer patients. These results suggest that AV biofeedback has the potential for facilitating reproducible tumor motion towards achieving more accurate medical imaging and radiation therapy procedures.

  12. Relevant infrastructural alterations in a pancreatic neuroendocrine tumor: an insulinoma case.

    PubMed

    Mirancea, Gabriel-Valeriu; Moroşanu, Ana-Maria; Carniciu, Simona; Dima, Simona; Bacalbaşa, Nicolae; Popescu, Irinel; Ionescu-Tîrgovişte, Constantin; Mirancea, Nicolae

    2014-01-01

    In this study, we focus our interest on some peculiar infrastructural abnormalities detected in an insulinoma case. Tumor pancreatic endocrine cells proliferated detrimental to exocrine counterpart, so that extensive areas of prevalent β-tumor cells can be seen. Two phenotypes of β-tumor cells can be identified: (1) β-tumor cells with full euchromatic and nucleolated nuclei and (2) β-tumor cells with heterochromatic and shrink nuclei. Because of stroma alteration, including basement membrane, cell-extracellular matrix junctions are also compromised. The mostly striking and important finding in this report for a case of insulinoma is the high fragility of plasma membrane of both two phenotypes of β-tumor cells. Cell-cell junctions, especially desmosomal junctions are severely altered, almost missing, plasma membranes showed shedding membrane vesicles and extensive dissolutions leading to pseudo-syncytia formation. Extravasated blood cells, including inflammatory cells contribute to the dramatic and extensive destructive areas of epithelial cells as well as stroma counterpart. Moreover, also the inner cell cytomembranes exhibit abnormalities: many β-tumor cells have excessive dilatations of nuclear envelope and endoplasmic reticulum. All above severe infrastructural abnormalities, especially down regulation of cell-cell and cell-extracellular matrix adhesions and plasma membranes fragility might result in aberrant cell behavior and, consequently, much care should be taken for the postoperatory patient evolution.

  13. Geometric uncertainty of 2D projection imaging in monitoring 3D tumor motion.

    PubMed

    Suh, Yelin; Dieterich, Sonja; Keall, Paul J

    2007-06-21

    The purpose of this study was to investigate the accuracy of two-dimensional (2D) projection imaging methods in three-dimensional (3D) tumor motion monitoring. Many commercial linear accelerator types have projection imaging capabilities, and tumor motion monitoring is useful for motion inclusive, respiratory gated or tumor tracking strategies. Since 2D projection imaging is limited in its ability to resolve the motion along the imaging beam axis, there is unresolved motion when monitoring 3D tumor motion. From the 3D tumor motion data of 160 treatment fractions for 46 thoracic and abdominal cancer patients, the unresolved motion due to the geometric limitation of 2D projection imaging was calculated as displacement in the imaging beam axis for different beam angles and time intervals. The geometric uncertainty to monitor 3D motion caused by the unresolved motion of 2D imaging was quantified using the root-mean-square (rms) metric. Geometric uncertainty showed interfractional and intrafractional variation. Patient-to-patient variation was much more significant than variation for different time intervals. For the patient cohort studied, as the time intervals increase, the rms, minimum and maximum values of the rms uncertainty show decreasing tendencies for the lung patients but increasing for the liver and retroperitoneal patients, which could be attributed to patient relaxation. Geometric uncertainty was smaller for coplanar treatments than non-coplanar treatments, as superior-inferior (SI) tumor motion, the predominant motion from patient respiration, could be always resolved for coplanar treatments. Overall rms of the rms uncertainty was 0.13 cm for all treatment fractions and 0.18 cm for the treatment fractions whose average breathing peak-trough ranges were more than 0.5 cm. The geometric uncertainty for 2D imaging varies depending on the tumor site, tumor motion range, time interval and beam angle as well as between patients, between fractions and within a

  14. Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer.

    PubMed

    Hoshi, Hirotaka; Sawada, Tetsuji; Uchida, Motoyuki; Saito, Hikaru; Iijima, Hiroko; Toda-Agetsuma, Mikako; Wada, Tsutomu; Yamazoe, Sadaaki; Tanaka, Hiroaki; Kimura, Kenjiro; Kakehashi, Anna; Wei, Min; Hirakawa, Kosei; Wanibuchi, Hideki

    2011-03-01

    MUC5AC, a high molecular weight glycoprotein, is overexpressed in the ductal region of human pancreatic cancer but is not detectable in the normal pancreas, suggesting its association with disease development. In the present study, we investigated the in vitro and in vivo effects of MUC5AC knockdown by short interfering RNA (siRNA) in the MUC5AC-overexpressing SW1990 and BxPC3 human pancreatic cancer cell lines in order to clarify its function. Significant decreases in the expression levels of MUC5AC mRNA and protein were observed in SW1990 and BxPC3 cells that had been stably transfected with a MUC5AC siRNA expression vector (SW1990/si-MUC5AC and BxPC3/si-MUC5AC cells) compared to those in cells transfected with an si-mock vector (SW1990/si-mock and BxPC3/si-mock cells). In in vitro studies, neither type of MUC5AC-knockdown cell showed any difference in cell survival, proliferation, or morphology from the si-mock cells or parental cells. However, in vivo xenograft studies demonstrated that MUC5AC knockdown significantly reduced the tumorigenicity and suppressed the tumor growth of si-MUC5AC cells compared to those of the si-mock cells. Immunohistochemical analysis revealed that CD45R/B220+ and Gr-1+ cells had infiltrated into the tumor tissue of the SW1990/si-MUC5AC cells. Furthermore, cancer-associated antigen specific antibodies were detected at high levels in the sera from the SW1990/si-MUC5AC cell-bearing mice. These results suggest that tumor-associated MUC5AC expressed on the surface of pancreatic cancer cells supports the escape of pancreatic cancer cells from immunosurveillance. The present findings highlight a new dimension of MUC5AC as a functional immunosuppressive agent and its important role in pancreatic cancer progression.

  15. Intraductal papillary-mucinous tumor of the pancreas head with complete absence of the ventral pancreatic duct of Wirsung.

    PubMed

    Sakurai, Yoichi; Matsubara, Toshiki; Imazu, Hiroki; Hasegawa, Shigeru; Miyakawa, Shuichi; Ochiai, Masahiro; Funabiki, Takahiko; Mizoguchi, Yoshikazu; Kuroda, Makoto

    2004-01-01

    A case of intraductal papillary mucinous tumor of the pancreas with complete absence of the ventral pancreatic duct of Wirsung is presented. A 74-year-old Japanese man was admitted to our hospital because of elevated serum amylase concentration. Abdominal computed tomography (CT) scanning revealed diffuse dilatation of the main pancreatic duct and a diffuse and uncircumscribed area with heterogeneous density in the pancreas head. Endoscopic retrograde cholangiopancreatography revealed that the main pancreatic duct was connected with an accessory papilla and was diffusely dilated, without any irregularity of the duct wall being observed in the entire length of the duct. The common bile duct was detected only by cannulation through Vater's papilla, and no pancreatic duct or its communicating branch was found. Some branches, directed to the dorsal portion of the pancreas head, were found arising from the accessory pancreatic duct. Intraductal ultrasound examination performed through the accessory papilla and the common bile duct revealed a small tumor with a heterogeneous echo level in the pancreas head. From these findings, intraductal papillary-mucinous tumor (IPMT) occurring in the pancreas head was diagnosed, and pylorus-preserving pancreaticoduodenectomy was performed. The resected specimen revealed IPMT in the pancreas head. A roentgenographic study of the resected specimen revealed a defect caused by the tumor located in the pancreatic duct connected with the accessory papilla and showed that there was complete absence of the pancreatic duct connected with Vater's papilla. Surgical resection enabled us to completely analyze the duct system of pancreas divisum. Although it is not known whether there is a relationship between the pathogenesis of IPMT and embryological anomaly of the pancreatic duct system, this case may provide an insight into the pathogenesis of IPMT.

  16. Targeted Disruption of Orchestration between Stroma and Tumor Cells in Pancreatic Cancer: Molecular Basis and Therapeutic Implications

    PubMed Central

    Kong, Xiangyu; Li, Lei; Li, Zhaoshen; Xie, Keping

    2012-01-01

    Pancreatic cancer is one of the most lethal malignancies, with a prominent desmoplastic reaction as the defining hallmark of the disease. The past several decades have seen dramatic progress in understanding of pancreatic cancer pathogenesis, including the identification of precursor lesions, sequential transformation from normal pancreas to invasive pancreatic cancer and corresponding signature genetic events, and the biological impact of those alterations on malignant behaviors. However, the current therapeutic strategies for epithelial tumor cells, which have exhibited potent antitumor activity in cell culture and animal models, have failed to have significant effects in the clinic. The desmoplastic stroma surrounding pancreatic cancer cells, which accounts for about 90% of a tumor’s mass, clearly is not a passive scaffold for cancer cells but an active contributor to carcinogenesis. Improved understanding of the dynamic interaction between cancer cells and their stroma will be important to designing new, effective therapeutic strategies for pancreatic cancer. This review focuses on the origination of stromal molecular and cellular components in pancreatic tumors, their biological effects on pancreatic cancer cells, and the orchestration between these two components. PMID:22749856

  17. Monoclonal Antibody 16D10 to the C-Terminal Domain of the Feto-Acinar Pancreatic Protein Binds to Membrane of Human Pancreatic Tumoral SOJ-6 Cells and Inhibits the Growth of Tumor Xenografts1

    PubMed Central

    Panicot-Dubois, Laurence; Aubert, Muriel; Franceschi, Cécile; Mas, Eric; Silvy, Françoise; Crotte, Christian; Bernard, Jean-Paul; Lombardo, Dominique; Sadoulet, Marie-Odile

    2004-01-01

    Abstract Feto-acinar pancreatic protein (FAPP) characterized by mAbJ28 reactivity is a specific component associated with ontogenesis and behaves as an oncodevelopment-associated antigen. We attempted to determine whether pancreatic tumoral SOJ-6 cells are expressed at their surface FAPP antigens and to examine if specific antibodies directed against these FAPP epitopes could decrease the growth of pancreatic tumors in a mice model. For this purpose, we used specific antibodies against either the whole FAPP, the O-glycosylated C-terminal domain, or the N-terminal domain of the protein. Our results indicate that SOJ-6 cells expressed at their surface a 32-kDa peptide corresponding to the C-terminal domain of the FAPP. Furthermore, we show, by using endoproteinase Lys-C or geldanamycin, a drug able to impair the FAPP secretion, that this 32-kDa peptide expressed on the SOJ-6 cell surface comes from the degradation of the FAPP. Finally, an in vivo prospective study using a preventative tumor model in nude mice indicates that targeting this peptide by the use of mAb16D10 inhibits the growth of SOJ-6 xenografts. The specificity of mAb16D10 for pancreatic tumors and the possibility to obtain recombinant structures of mucin-like peptides recognized by mAb16D10 and mAbJ28 are promising tools in immunologic approaches to cure pancreatic cancers. PMID:15720797

  18. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular-fibrosis and tumor progression

    PubMed Central

    Laklai, Hanane; Miroshnikova, Yekaterina A.; Pickup, Michael W.; Collisson, Eric A.; Kim, Grace E.; Barrett, Alex S.; Hill, Ryan C.; Lakins, Johnathon N.; Schlaepfer, David D.; Mouw, Janna K.; LeBleu, Valerie S.; Roy, Nilotpal; Novitskiy, Sergey V.; Johansen, Julia S.; Poli, Valeria; Kalluri, Raghu; Iacobuzio-Donahue, Christine A.; Wood, Laura D.; Hebrok, Matthias; Hansen, Kirk; Moses, Harold L.; Weaver, Valerie M.

    2016-01-01

    Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality yet anti-stromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor β (TGF-β) signaling have elevated epithelial Stat3 activity and develop a stiffer, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several Kras-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby Stat3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial Stat3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated Stat3 associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors, and highlight Stat3 and mechanics as key drivers of this phenotype. PMID:27089513

  19. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis.

    PubMed

    Kim, Haeryoung; Saka, Burcu; Knight, Spencer; Borges, Michael; Childs, Erica; Klein, Alison; Wolfgang, Christopher; Herman, Joseph; Adsay, Volkan N; Hruban, Ralph H; Goggins, Michael

    2014-04-01

    To determine how often loss of ataxia-telangiectasia-mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27-5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response. Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection. ©2014 AACR.

  20. Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis

    PubMed Central

    Kim, Haeryoung; Saka, Burcu; Knight, Spencer; Borges, Michael; Childs, Erica; Klein, Alison; Wolfgang, Christopher; Herman, Joseph; Adsay, Volkan N.; Hruban, Ralph H.; Goggins, Michael

    2014-01-01

    Purpose To determine how often loss of ATM protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. Experimental Design The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically-resected pancreatic ductal adenocarcinomas (Hopkins), a second set of 159 cases (Emory) and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. Results Tumoral ATM loss was observed in one cancer known to have bi-allelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%) (p=0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (p=0.019) and was a significant independent predictor of decreased overall survival (p=0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (p=0.1). Multivariate analysis of the combined Hopkins/Emory cases found tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival (HR 2.61, CI1.27–5.37, p=0.009). Of 21 cancers examined after neoadjuvant chemoradiotherapy one had tumoral loss of ATM; it had no histological evidence of tumor response. Conclusions Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection. PMID:24486587

  1. 64-Slice spiral computed tomography and three-dimensional reconstruction in the diagnosis of cystic pancreatic tumors

    PubMed Central

    WEN, ZHAOXIA; YAO, FENGQING; WANG, YUXING

    2016-01-01

    The present study aimed to describe the characteristics of cystic pancreatic tumors using computed tomography (CT) and to evaluate the diagnostic accuracy (DA) of post-imaging three-dimensional (3D) reconstruction. Clinical and imaging data, including multi-slice spiral CT scans, enhanced scans and multi-faceted reconstruction, from 30 patients with pathologically confirmed cystic pancreatic tumors diagnosed at the Linyi People's Hospital between August 2008 and June 2014 were retrospectively analyzed. Following the injection of Ultravist® 300 contrast agent, arterial, portal venous and parenchymal phase scans were obtained at 28, 60 and 150 sec, respectively, and 3D reconstructions of the CT images were generated. The average age of the patients was 38.4 years (range, 16–77 years), and the cohort included 5 males and 25 females (ratio, 1:5). The patients included 8 cases of mucinous cystadenoma (DA), 80%]; 9 cases of cystadenocarcinoma (DA, 84%); 6 cases of serous cystadenoma (DA, 100%); 3 cases of solid pseudopapillary tumor (DA, 100%); and 4 cases of intraductal papillary mucinous neoplasm (DA, 100%). 3D reconstructions of CT images were generated and, in the 4 cases of intraductal papillary mucinous neoplasm, the tumor was connected to the main pancreatic duct and multiple mural nodules were detected in one of these cases. The DA of the 3D-reconstructed images of cystic pancreatic tumors was 89.3%. The 64-slice spiral CT and 3D-reconstructed CT images facilitated the visualization of cystic pancreatic tumor characteristics, in particular the connections between the tumor and the main pancreatic duct. In conclusion, the 3D reconstruction of multi-slice CT data may provide an important source of information for the surgical team, in combination with the available clinical data. PMID:27073473

  2. Local pressure and matrix component effects on verteporfin distribution in pancreatic tumors (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Nieskoski, Michael D.; Marra, Kayla; Gunn, Jason R.; Doyley, Marvin; Samkoe, Kimberly S.; Pereira, Stephen P.; Trembly, B. Stuart; Pogue, Brian W.

    2017-02-01

    Pancreatic tumors are characterized by large interstitial hypertension from enhanced deposition of extracellular matrix components, resulting in widespread vascular collapse and reduced molecular uptake of systemically delivered therapies. Although the origins of hypoperfusion is debated amongst researchers, spatial distribution of collagen density and hyaluronic acid content have shown to be a key metric in understanding the lack of efficacy for both acute and chronic therapies in these tumors. In this study, the AsPC-1 tumor model was used both subcutaneously and orthotopically to study the measurable factors which are related to this. A conventional piezoelectric pressure catheter was used to measure total tissue pressure (TTP), defined as a combination of solid stress (SS) and interstitial fluid pressure (IFP), TTP = SS + IFP, in multiple locations within the tumor interstitium. Matrix components such as collagen and hyaluronic acid were scored using masson's trichrome stain and hyaluronic acid binding protein (HABP), respectively, and co-registered with values of TTP. The results show that these key measurements are related to the spatial distribution of verteporfin in the same tumors. Photodynamic treatment with verteporfin is known to ablate large regions of tumor tissue and also allow better permeability for chemotherapies. The study of spatial distribution of verteporfin in relation to stromal content and TTP will help us better control these types of combination therapies.

  3. Proteomic analysis of pancreatic endocrine tumor cell lines treated with the histone deacetylase inhibitor trichostatin A.

    PubMed

    Cecconi, Daniela; Donadelli, Massimo; Rinalducci, Sara; Zolla, Lello; Scupoli, Maria Teresa; Scarpa, Aldo; Palmieri, Marta; Righetti, Pier Giorgio

    2007-05-01

    Effects of the histone-deacetylases inhibitor trichostatin A (TSA) on the growth of three different human pancreatic endocrine carcinoma cell lines (CM, BON, and QGP-1) have been assessed via dosage-dependent growth inhibition curves. TSA determined strong inhibition of cell growth with similar IC(50) values for the different cell lines: 80.5 nM (CM), 61.6 nM (BON), and 86 nM (QGP-1), by arresting the cell cycle in G2/M phase and inducing apoptosis. 2DE and nano-RP-HPLC-ESI-MS/MS analysis revealed 34, 33, and 38 unique proteins differentially expressed after TSA treatment in the CM, BON, and QGP-1 cell lines, respectively. The most important groups of modulated proteins belong to cell proliferation, cell cycle, and apoptosis classes (such as peroxiredoxins 1 and 2, the diablo protein, and HSP27). Other proteins pertain to processes such as regulation of gene expression (nucleophosmin, oncoprotein dek), signal transduction (calcium-calmodulin), chromatin, and cytoskeleton organization (calgizzarin, dynein, and lamin), RNA splicing (nucleolin, HNRPC), and protein folding (HSP70). The present data are in agreement with previous proteomic analyses performed on pancreatic ductal carcinoma cell lines (Cecconi, D. et al.., Electrophoresis 2003; Cecconi, D. et al., J. Proteome Res. 2005) and place histone-deacetylases inhibitors among the potentially most powerful drugs for the treatment of pancreatic tumors.

  4. Capsaicin induces cytotoxicity in pancreatic neuroendocrine tumor cells via mitochondrial action.

    PubMed

    Skrzypski, M; Sassek, M; Abdelmessih, S; Mergler, S; Grötzinger, C; Metzke, D; Wojciechowicz, T; Nowak, K W; Strowski, M Z

    2014-01-01

    Capsaicin (CAP), the pungent ingredient of chili peppers, inhibits growth of various solid cancers via TRPV1 as well as TRPV1-independent mechanisms. Recently, we showed that TRPV1 regulates intracellular calcium level and chromogranin A secretion in pancreatic neuroendocrine tumor (NET) cells. In the present study, we characterize the role of the TRPV1 agonist - CAP - in controlling proliferation and apoptosis of pancreatic BON and QGP-1 NET cells. We demonstrate that CAP reduces viability and proliferation, and stimulates apoptotic death of NET cells. CAP causes mitochondrial membrane potential loss, inhibits ATP synthesis and reduces mitochondrial Bcl-2 protein production. In addition, CAP increases cytochrome c and cleaved caspase 3 levels in cytoplasm. CAP reduces reactive oxygen species (ROS) generation. The antioxidant N-acetyl-l-cysteine (NAC) acts synergistically with CAP to reduce ROS generation, without affecting CAP-induced toxicity. TRPV1 protein reduction by 75% reduction fails to attenuate CAP-induced cytotoxicity. In summary, these results suggest that CAP induces cytotoxicity by disturbing mitochondrial potential, and inhibits ATP synthesis in NET cells. Stimulation of ROS generation by CAP appears to be a secondary effect, not related to CAP-induced cytotoxicity. These results justify further evaluation of CAP in modulating pancreatic NETs in vivo.

  5. Resected Pancreatic Neuroendocrine Tumors: Patterns of Failure and Disease-Related Outcomes With or Without Radiotherapy

    SciTech Connect

    Zagar, Timothy M.; White, Rebekah R.; Willett, Christopher G.; Tyler, Douglas S.; Papavassiliou, Paulie; Papalezova, Katia T.; Guy, Cynthia D.; Broadwater, Gloria; Clough, Robert W.; Czito, Brian G.

    2012-07-15

    Purpose: Pancreatic neuroendocrine tumors (NET) are rare and have better disease-related outcomes compared with pancreatic adenocarcinoma. Surgical resection remains the standard of care, although many patients present with locally advanced or metastatic disease. Little is known regarding the use of radiotherapy in the prevention of local recurrence after resection. To better define the role of radiotherapy, we performed an analysis of resected patients at our institution. Methods: Between 1994 and 2009, 33 patients with NET of the pancreatic head and neck underwent treatment with curative intent at Duke University Medical Center. Sixteen patients were treated with surgical resection alone while an additional 17 underwent resection with adjuvant or neoadjuvant radiation therapy, usually with concurrent fluoropyrimidine-based chemotherapy (CMT). Median radiation dose was 50.4 Gy and median follow-up 28 months. Results: Thirteen patients (39%) experienced treatment failure. Eleven of the initial failures were distant, one was local only and one was local and distant. Two-year overall survival was 77% for all patients. Two-year local control for all patients was 87%: 85% for the CMT group and 90% for the surgery alone group (p = 0.38). Two-year distant metastasis-free survival was 56% for all patients: 46% and 69% for the CMT and surgery patients, respectively (p = 0.10). Conclusions: The primary mode of failure is distant which often results in mortality, with local failure occurring much less commonly. The role of radiotherapy in the adjuvant management of NET remains unclear.

  6. En Masse Resection of Pancreas, Spleen, Celiac Axis, Stomach, Kidney, Adrenal, and Colon for Invasive Pancreatic Corpus and Tail Tumor

    PubMed Central

    Kutluturk, Koray; Alam, Abdul Hamid; Kayaalp, Cuneyt; Otan, Emrah; Aydin, Cemalettin

    2013-01-01

    Providing a more comfortable life and a longer survival for pancreatic corpus/tail tumors without metastasis depends on the complete resection. Recently, distal pancreatectomy with celiac axis resection was reported as a feasible and favorable method in selected pancreatic corpus/tail tumors which had invaded the celiac axis. Additional organ resections to the celiac axis were rarely required, and when necessary it was included only a single extra organ resection such as adrenal or intestine. Here, we described a distal pancreatic tumor invading most of the neighboring organs—stomach, celiac axis, left renal vein, left adrenal gland, and splenic flexure were treated by en bloc resection of all these organs. The patient was a 60-year-old man without any severe medical comorbidities. Postoperative course of the patient was uneventful, and he was discharged on postoperative day eight without any complication. Histopathology and stage of the tumor were adenocarcinoma and T4 N1 M0, respectively. Preoperative back pain of the patient was completely relieved in the postoperative period. As a result, celiac axis resection for pancreatic cancer is an extensive surgery, and a combined en masse resection of the invaded neighboring organs is a more extensive surgery than the celiac axis resection alone. This more extensive surgery is safe and feasible for selected patients with pancreatic cancer. PMID:24159408

  7. En masse resection of pancreas, spleen, celiac axis, stomach, kidney, adrenal, and colon for invasive pancreatic corpus and tail tumor.

    PubMed

    Kutluturk, Koray; Alam, Abdul Hamid; Kayaalp, Cuneyt; Otan, Emrah; Aydin, Cemalettin

    2013-01-01

    Providing a more comfortable life and a longer survival for pancreatic corpus/tail tumors without metastasis depends on the complete resection. Recently, distal pancreatectomy with celiac axis resection was reported as a feasible and favorable method in selected pancreatic corpus/tail tumors which had invaded the celiac axis. Additional organ resections to the celiac axis were rarely required, and when necessary it was included only a single extra organ resection such as adrenal or intestine. Here, we described a distal pancreatic tumor invading most of the neighboring organs-stomach, celiac axis, left renal vein, left adrenal gland, and splenic flexure were treated by en bloc resection of all these organs. The patient was a 60-year-old man without any severe medical comorbidities. Postoperative course of the patient was uneventful, and he was discharged on postoperative day eight without any complication. Histopathology and stage of the tumor were adenocarcinoma and T4 N1 M0, respectively. Preoperative back pain of the patient was completely relieved in the postoperative period. As a result, celiac axis resection for pancreatic cancer is an extensive surgery, and a combined en masse resection of the invaded neighboring organs is a more extensive surgery than the celiac axis resection alone. This more extensive surgery is safe and feasible for selected patients with pancreatic cancer.

  8. Radiolabeling of substance P with lutetium-177 and biodistribution study in rat pancreatic tumor xenografted nude mice.

    PubMed

    De Araújo, E B; Pujatti, P B; Mengatti, J

    2010-05-10

    Pancreatic tumor (PT) is a neuroendocrine neoplasm that usually origin metastases in the respiratory and gastrointestinal tract. The presence of peptide receptors at the cell membrane of PT constitutes the basis of the clinical use of specific radiolabeled ligands for its diagnosis and targeted therapy. Substance P (SP), an 11-amino acid peptide which has an important role in modulating pain transmission trough neurokinin type 1 (NK1r) and 2 receptors (NK2r), may play a role in the pathogenesis of PT, because approximately 10% of these tumors overexpress NK1r. The aim of the present work was to produce a pure and stable SP analog (DOTA-SP) radiolabeled with lutetium-177 ((177)Lu), and to evaluate its in vivo target to AR42J pancreatic tumor cells in Nude mice, in other to verify if SP can be used in this pancreatic tumor detection and treatment. Substance P was successfully labeled with high yield (>99%) at optimized conditions and kept stable for more than 72 hours at 2-8 degrees C and 4 hours in human plasma. Biodistribution studies showed that SP excretion was mainly performed by renal pathway. In addition, (177)Lu-DOTA-SP showed higher uptake by tumor than normal pancreas, indicating the presence of NK receptors in AR42J pancreatic tumor.

  9. Characterization of pancreatic glucagon-producing tumors and pituitary gland tumors in transgenic mice overexpressing MYCN in hGFAP-positive cells

    PubMed Central

    Fielitz, Kathrin; Althoff, Kristina; De Preter, Katleen; Nonnekens, Julie; Ohli, Jasmin; Elges, Sandra; Hartmann, Wolfgang; Klöppel, Günter; Knösel, Thomas; Schulte, Marc; Klein-Hitpass, Ludger; Beisser, Daniela; Reis, Henning; Eyking, Annette; Cario, Elke; Schulte, Johannes H.

    2016-01-01

    Amplification or overexpression of MYCN is involved in development and maintenance of multiple malignancies. A subset of these tumors originates from neural precursors, including the most aggressive forms of the childhood tumors, neuroblastoma and medulloblastoma. In order to model the spectrum of MYCN-driven neoplasms in mice, we transgenically overexpressed MYCN under the control of the human GFAP-promoter that, among other targets, drives expression in neural progenitor cells. However, LSL-MYCN;hGFAP-Cre double transgenic mice did neither develop neural crest tumors nor tumors of the central nervous system, but presented with neuroendocrine tumors of the pancreas and, less frequently, the pituitary gland. Pituitary tumors expressed chromogranin A and closely resembled human pituitary adenomas. Pancreatic tumors strongly produced and secreted glucagon, suggesting that they derived from glucagon- and GFAP-positive islet cells. Interestingly, 3 out of 9 human pancreatic neuroendocrine tumors expressed MYCN, supporting the similarity of the mouse tumors to the human system. Serial transplantations of mouse tumor cells into immunocompromised mice confirmed their fully transformed phenotype. MYCN-directed treatment by AuroraA- or Brd4-inhibitors resulted in significantly decreased cell proliferation in vitro and reduced tumor growth in vivo. In summary, we provide a novel mouse model for neuroendocrine tumors of the pancreas and pituitary gland that is dependent on MYCN expression and that may help to evaluate MYCN-directed therapies. PMID:27769070

  10. Radio frequency-mediated local thermotherapy for destruction of pancreatic tumors using Ni-Au core-shell nanowires

    NASA Astrophysics Data System (ADS)

    Hopkins, Xiaoping; Gill, Waqas Amin; Kringel, Rosemarie; Wang, Guankui; Hass, Jamie; Acharya, Suresh; Park, Jungrae; Tak Jeon, In; An, Boo Hyun; Lee, Ji Sung; Ryu, Jong Eun; Hill, Rod; McIlroy, David; Kim, Young Keun; Choi, Daniel S.

    2017-01-01

    We present a novel method of radio frequency (RF)-mediated thermotherapy in tumors by remotely heating nickel (Ni)-gold (Au) core-shell nanowires (CSNWs). Ectopic pancreatic tumors were developed in nude mice to evaluate the thermotherapeutic effects on tumor progression. Tumor ablation was produced by RF-mediated thermotherapy via activation of the paramagnetic properties of the Ni-Au CSNWs. Histopathology demonstrated that heat generated by RF irradiation caused significant cellular death with pyknotic nuclei and nuclear fragmentation dispersed throughout the tumors. These preliminary results suggest that thermotherapy ablation induced via RF activation of nanowires provides a potential alternative therapy for cancer treatment.

  11. Pancreatic extragastrointestinal stromal tumor: A case report and comprehensive literature review

    PubMed Central

    Akbulut, Sami; Yavuz, Rıdvan; Otan, Emrah; Hatipoglu, Sinan

    2014-01-01

    AIM: To provide an overview of the literature on pancreatic extragastrointestinal stromal tumors (EGISTs). METHODS: We report a case of pancreatic EGIST and review published studies on pancreatic EGIST accessed via the PubMed, MEDLINE, Google Scholar, and Google databases. The keywords used were “pancreas and GIST”, “pancreas and extra GIST”, “pancreas and gastrointestinal stromal tumor”, and “pancreas and extragastrointestinal stromal tumor”. Literature reviews and/or duplicate studies were excluded. The search included articles published in the English language between January 1, 2000 and May 15, 2014. RESULTS: From our literature survey, 30 manuscripts on pancreatic EGISTs were considered, of which 27 met the search criteria and three were excluded. The studies involved 30 patients (15 men, 15 women) with a mean age of 55.3 ± 14.3 years (range 30-84 years). The mean age of the male patients was 50.8 ± 13.7 years (range 30-84 years); that of the female patients was 59.9 ± 13.3 years (range 38-81 years). Tumor dimensions were obtained for 28 cases (mean 114.4 ± 78.6 mm; range 20-350 mm). Tumors were diagnosed incidentally in 23.3% of patients; abdominal discomfort and weight loss were the major complaints in symptomatic patients. Risk of aggressive behavior according to Fletcher criteria was determined in 25 of 30 patients (68%: high risk, 28%: intermediate risk, 4%: low risk). Histopathological examination revealed the presence of spindle cells in 96.1% of cases; CD117 and CD34 were present immunohistochemically in 96.6% and 84% of patients, respectively. The most common surgical procedures were distal pancreatectomy with splenectomy (n = 9) and pancreaticoduodenectomy (n = 7). The total follow-up period for the 28 patients ranged from 3-66 mo, during which locoregional or distant metastases were diagnosed in six patients and two patients died. CONCLUSION: Studies on EGISTs have only been published in the last decade. The lack of studies with

  12. The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma

    PubMed Central

    Liu, Rui; Zhang, Haiyang; Wang, Xia; Zhou, Likun; Li, Hongli; Deng, Ting; Qu, Yanjun; Duan, Jingjing; Bai, Ming; Ge, Shaohua; Ning, Tao; Zhang, Le

    2015-01-01

    miRNAs are a group of small RNAs that have been reported to play a key role at each stage of tumorigenesis and are believed to have future practical value. We now demonstrate that Bim, which stimulates cell apoptosis, is obviously down-regulated in pancreatic cancer (PaC) tissues and cell lines. And Bim-related miR-24 is significantly up-regulated in PaC. The repressed expression of Bim is proved to be a result of miR-24, thus promoting cell growth of both cancer and vascular cells, and accelerating vascular ring formation. By using mouse tumor model, we clearly showed that miR-24 promotes tumor growth and angiogenesis by suppressing Bim expression in vivo. Therefore, a new pathway comprising miR-24 and Bim can be used in the exploration of drug-target therapy of PaC. PMID:26517093

  13. Future Directions in the Treatment of Gastrointestinal and Pancreatic Neuroendocrine Tumors.

    PubMed

    Asmis, Timothy

    2016-07-01

    Recently, the landscape of the diagnosis and treatment of patients with well-differentiated gastrointestinal/pancreatic neuroendocrine tumors (previously referred to as carcinoid tumors) has changed dramatically. We will need to work with all of the stakeholders including clinicians, patients, regulatory agencies, and industry to best navigate future treatment and research. Future protocols will require us to define clinically relevant end points. In designing future clinical trials, we will need to determine which patients will be included in these studies. Future research will need to address the best way to image and follow patient's disease both in the clinic and on research studies. Timely access to new therapies will be the utmost importance to both current and future patients. We must work together to establish relevant clinical questions and to pursue collaborative research that promotes the health of our patients.

  14. Improving pancreatic cancer diagnosis using circulating tumor cells: prospects for staging and single-cell analysis

    PubMed Central

    Court, Colin M; Ankeny, Jacob S; Hou, Shuang; Tseng, Hsian-Rong; Tomlinson, James S

    2016-01-01

    Pancreatic cancer (PC) is the fourth most common cause of cancer-related death in the USA, primarily due to late presentation coupled with an aggressive biology. The lack of adequate biomarkers for diagnosis and staging confound clinical decision-making and delay potentially effective therapies. Circulating tumor cells (CTCs) are a promising new biomarker in PC. Preliminary studies have demonstrated their potential clinical utility, and newer CTC isolation platforms have the potential to provide clinicians access to tumor tissue in a reliable, real-time manner. Such a ‘liquid biopsy’ has been demonstrated in several cancers, and small studies have demonstrated its potential applications in PC. This article reviews the available literature on CTCs as a biomarker in PC and presents the latest innovations in CTC research as well as their potential applications in PC. PMID:26390158

  15. Gastro-entero-pancreatic neuroendocrine tumors: Is now time for a new approach?

    PubMed

    Berardi, Rossana; Torniai, Mariangela; Savini, Agnese; Rinaldi, Silvia; Cascinu, Stefano

    2016-04-10

    Gastro-entero-pancreatic tumors (GEP-NETs) are rare neoplasms often characterized by an overexpression of somatostatin receptors. Thus, radiolabeled somatostatin analogues have showed an increasing relevance both in diagnosis and treatment, especially in low- and intermediate-differentiated GEP-NETs. These evidences have led to a growing development of new functional imaging techniques as 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) proved useful in the management of these neoplasms. However these tumors have a heterogeneous behavior also modifying their aggressiveness through time. Therefore sometimes 18F-fluorodeoxyglucose PET/CT appears to be more appropriate to obtain a better assessment of the disease. According to these considerations, the combination of different functional imaging techniques should be considered in the management of GEP-NETs patients allowing clinicians to choose the tailored therapeutic approach among available options.

  16. The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma.

    PubMed

    Liu, Rui; Zhang, Haiyang; Wang, Xia; Zhou, Likun; Li, Hongli; Deng, Ting; Qu, Yanjun; Duan, Jingjing; Bai, Ming; Ge, Shaohua; Ning, Tao; Zhang, Le; Huang, Dingzhi; Ba, Yi

    2015-12-22

    miRNAs are a group of small RNAs that have been reported to play a key role at each stage of tumorigenesis and are believed to have future practical value. We now demonstrate that Bim, which stimulates cell apoptosis, is obviously down-regulated in pancreatic cancer (PaC) tissues and cell lines. And Bim-related miR-24 is significantly up-regulated in PaC. The repressed expression of Bim is proved to be a result of miR-24, thus promoting cell growth of both cancer and vascular cells, and accelerating vascular ring formation. By using mouse tumor model, we clearly showed that miR-24 promotes tumor growth and angiogenesis by suppressing Bim expression in vivo. Therefore, a new pathway comprising miR-24 and Bim can be used in the exploration of drug-target therapy of PaC.

  17. Rapid dramatic alterations to the tumor microstructure in pancreatic cancer following irreversible electroporation ablation

    PubMed Central

    Zhang, Zhuoli; Li, Weiguo; Procissi, Daniel; Tyler, Patrick; Omary, Reed A; Larson, Andrew C

    2013-01-01

    Aim NanoKnife® (Angiodynamics, Inc., NY, USA) or irreversible electroporation (IRE) is a newly available ablation technique to induce the formation of nanoscale pores within the cell membrane in targeted tissues. The purpose of this study was to elucidate morphological alterations following 30 min of IRE ablation in a mouse model of pancreatic cancer. Materials & methods Immunohistochemistry markers were compared with diffusion-weighted MRI apparent diffusion coefficient measurements before and after IRE ablation. Results Immunohistochemistry apoptosis index measurements were significantly higher in IRE-treated tumors than in controls. Rapid tissue alterations after 30 min of IRE ablation procedures (structural and morphological alterations along with significantly elevated apoptosis markers) were consistently observed and well correlated to apparent diffusion coefficient measurements. Discussion This imaging assay offers the potential to serve as an in vivo biomarker for noninvasive detection of tumor response following IRE ablation. PMID:24024571

  18. Model-based risk assessment for motion effects in 3D radiotherapy of lung tumors

    NASA Astrophysics Data System (ADS)

    Werner, René; Ehrhardt, Jan; Schmidt-Richberg, Alexander; Handels, Heinz

    2012-02-01

    Although 4D CT imaging becomes available in an increasing number of radiotherapy facilities, 3D imaging and planning is still standard in current clinical practice. In particular for lung tumors, respiratory motion is a known source of uncertainty and should be accounted for during radiotherapy planning - which is difficult by using only a 3D planning CT. In this contribution, we propose applying a statistical lung motion model to predict patients' motion patterns and to estimate dosimetric motion effects in lung tumor radiotherapy if only 3D images are available. Being generated based on 4D CT images of patients with unimpaired lung motion, the model tends to overestimate lung tumor motion. It therefore promises conservative risk assessment regarding tumor dose coverage. This is exemplarily evaluated using treatment plans of lung tumor patients with different tumor motion patterns and for two treatment modalities (conventional 3D conformal radiotherapy and step-&- shoot intensity modulated radiotherapy). For the test cases, 4D CT images are available. Thus, also a standard registration-based 4D dose calculation is performed, which serves as reference to judge plausibility of the modelbased 4D dose calculation. It will be shown that, if combined with an additional simple patient-specific breathing surrogate measurement (here: spirometry), the model-based dose calculation provides reasonable risk assessment of respiratory motion effects.

  19. A study of longitudinal tumor motion in helical tomotherapy using a cylindrical phantom.

    PubMed

    Klein, Michael; Gaede, Stewart; Yartsev, Slav

    2013-03-04

    Tumor motion during radiation treatment on a helical tomotherapy unit may create problems due to interplay with motion of the multileaf collimator, gantry rotation, and patient couch translation through the gantry. This study evaluated this interplay effect for typical clinical parameters using a cylindrical phantom consisting of 1386 diode detectors placed on a respiratory motion platform. All combinations of radiation field widths (1, 2.5, and 5 cm) and gantry rotation periods (16, 30, and 60 s) were considered for sinusoidal motions with a period of 4 s and amplitudes of 5, 6, 7, 8, 9, and 10 mm, as well as real patient breathing pattern. Gamma comparisons with 2% dose difference and 2 mm distance to agreement and dose profiles were used for evaluation. The required motion margins were determined for each set of parameters. The required margin size increased with decreasing field width and increasing tumor motion amplitude, but was not affected by rotation period. The plans with the smallest field width of 1 cm have required motion margins approximately equal to the amplitude of motion (± 25%), while those with the largest field width of 5 cm had required motion margins approximately equal to 20% of the motion amplitude (± 20%). For tumor motion amplitudes below 6 mm and field widths above 1 cm, the required additional motion margins were very small, at a maximum of 2.5 mm for sinusoidal breathing patterns and 1.2 mm for the real patient breathing pattern.

  20. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development

    PubMed Central

    Gironella, Meritxell; Seux, Mylène; Xie, Min-Jue; Cano, Carla; Tomasini, Richard; Gommeaux, Julien; Garcia, Stephane; Nowak, Jonathan; Yeung, Man Lung; Jeang, Kuan-Teh; Chaix, Amandine; Fazli, Ladan; Motoo, Yoshiharu; Wang, Qing; Rocchi, Palma; Russo, Antonio; Gleave, Martin; Dagorn, Jean-Charles; Iovanna, Juan L.; Carrier, Alice; Pébusque, Marie-Josèphe; Dusetti, Nelson J.

    2007-01-01

    Pancreatic cancer is a disease with an extremely poor prognosis. Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a proapoptotic stress-induced p53 target gene. In this article, we show by immunohistochemical analysis that TP53INP1 expression is dramatically reduced in pancreatic ductal adenocarcinoma (PDAC) and this decrease occurs early during pancreatic cancer development. TP53INP1 reexpression in the pancreatic cancer-derived cell line MiaPaCa2 strongly reduced its capacity to form s.c., i.p., and intrapancreatic tumors in nude mice. This anti-tumoral capacity is, at least in part, due to the induction of caspase 3-mediated apoptosis. In addition, TP53INP1−/− mouse embryonic fibroblasts (MEFs) transformed with a retrovirus expressing E1A/rasV12 oncoproteins developed bigger tumors than TP53INP1+/+ transformed MEFs or TP53INP1−/− transformed MEFs with restored TP53INP1 expression. Finally, TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in PDAC cells. TP53INP1 is a previously unknown miR-155 target presenting anti-tumoral activity. PMID:17911264

  1. Detecting circulating tumor material and digital pathology imaging during pancreatic cancer progression.

    PubMed

    Moravec, Radim; Divi, Rao; Verma, Mukesh

    2017-06-15

    Pancreatic cancer (PC) is a leading cause of cancer-related death worldwide. Clinical symptoms typically present late when treatment options are limited and survival expectancy is very short. Metastatic mutations are heterogeneous and can accumulate up to twenty years before PC diagnosis. Given such genetic diversity, detecting and managing the complex states of disease progression may be limited to imaging modalities and markers present in circulation. Recent developments in digital pathology imaging show potential for early PC detection, making a differential diagnosis, and predicting treatment sensitivity leading to long-term survival in advanced stage patients. Despite large research efforts, the only serum marker currently approved for clinical use is CA 19-9. Utility of CA 19-9 has been shown to improve when it is used in combination with PC-specific markers. Efforts are being made to develop early-screening assays that can detect tumor-derived material, present in circulation, before metastasis takes a significant course. Detection of markers that identify circulating tumor cells and tumor-derived extracellular vesicles (EVs) in biofluid samples offers a promising non-invasive method for this purpose. Circulating tumor cells exhibit varying expression of epithelial and mesenchymal markers depending on the state of tumor differentiation. This offers a possibility for monitoring disease progression using minimally invasive procedures. EVs also offer the benefit of detecting molecular cargo of tumor origin and add the potential to detect circulating vesicle markers from tumors that lack invasive properties. This review integrates recent genetic insights of PC progression with developments in digital pathology and early detection of tumor-derived circulating material.

  2. Detecting circulating tumor material and digital pathology imaging during pancreatic cancer progression

    PubMed Central

    Moravec, Radim; Divi, Rao; Verma, Mukesh

    2017-01-01

    Pancreatic cancer (PC) is a leading cause of cancer-related death worldwide. Clinical symptoms typically present late when treatment options are limited and survival expectancy is very short. Metastatic mutations are heterogeneous and can accumulate up to twenty years before PC diagnosis. Given such genetic diversity, detecting and managing the complex states of disease progression may be limited to imaging modalities and markers present in circulation. Recent developments in digital pathology imaging show potential for early PC detection, making a differential diagnosis, and predicting treatment sensitivity leading to long-term survival in advanced stage patients. Despite large research efforts, the only serum marker currently approved for clinical use is CA 19-9. Utility of CA 19-9 has been shown to improve when it is used in combination with PC-specific markers. Efforts are being made to develop early-screening assays that can detect tumor-derived material, present in circulation, before metastasis takes a significant course. Detection of markers that identify circulating tumor cells and tumor-derived extracellular vesicles (EVs) in biofluid samples offers a promising non-invasive method for this purpose. Circulating tumor cells exhibit varying expression of epithelial and mesenchymal markers depending on the state of tumor differentiation. This offers a possibility for monitoring disease progression using minimally invasive procedures. EVs also offer the benefit of detecting molecular cargo of tumor origin and add the potential to detect circulating vesicle markers from tumors that lack invasive properties. This review integrates recent genetic insights of PC progression with developments in digital pathology and early detection of tumor-derived circulating material. PMID:28656074

  3. Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD.

    PubMed

    Cortez, Eliane; Gladh, Hanna; Braun, Sebastian; Bocci, Matteo; Cordero, Eugenia; Björkström, Niklas K; Miyazaki, Hideki; Michael, Iacovos P; Eriksson, Ulf; Folestad, Erika; Pietras, Kristian

    2016-02-16

    Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.

  4. Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

    PubMed Central

    Cortez, Eliane; Gladh, Hanna; Braun, Sebastian; Bocci, Matteo; Cordero, Eugenia; Björkström, Niklas K.; Miyazaki, Hideki; Michael, Iacovos P.; Eriksson, Ulf; Folestad, Erika; Pietras, Kristian

    2016-01-01

    Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis. PMID:26831065

  5. Targeted oncolytic herpes simplex virus type 1 eradicates experimental pancreatic tumors.

    PubMed

    Gayral, Marion; Lulka, Hubert; Hanoun, Naima; Biollay, Coline; Sèlves, Janick; Vignolle-Vidoni, Alix; Berthommé, Hervé; Trempat, Pascal; Epstein, Alberto L; Buscail, Louis; Béjot, Jean-Luc; Cordelier, Pierre

    2015-02-01

    As many other cancers, pancreatic ductal adenocarcinoma (PDAC) progression is associated with a series of hallmark changes for cancer cells to secure their own growth success. Yet, these very changes render cancer cells highly sensitive to viral infection. A promising strategy may rely on and exploit viral replication for tumor destruction, whereby infection of tumor cells by a replication-conditional virus may lead to cell destruction and simultaneous release of progeny particles that can spread and infect adjacent tumor cells, while sparing healthy tissues. In the present study, we used Myb34.5, a second-generation replication-conditional herpes simplex virus type 1 (HSV-1) mutant in which ICP6 gene expression is defective and expression of the HSV-1 γ134.5 gene is regulated by the cellular B-myb promoter. We found that B-myb is present in experimental PDAC and tumors, and is overexpressed in patients' tumors, as compared with normal adjacent pancreas. Myb34.5 replicates to high level in human PDAC cell lines and is associated with cell death by apoptosis. In experimental models of PDAC, mice receiving intratumoral Myb34.5 injections appeared healthy and tumor progression was inhibited, with evidence of tumor necrosis, hemorrhage, viral replication, and cancer cell death by apoptosis. Combining standard-of-care chemotherapy with Myb34.5 successfully led to a very impressive antitumoral effect that is rarely achieved in this experimental model, and resulted in a greater reduction in tumor growth than chemotherapy alone. These promising results warrant further evaluation in early phase clinical trial for patients diagnosed with PDAC for whom no effective treatment is available.

  6. Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures.

    PubMed

    Mohamed, Amira; Blanchard, Marie-Pierre; Albertelli, Manuela; Barbieri, Federica; Brue, Thierry; Niccoli, Patricia; Delpero, Jean-Robert; Monges, Genevieve; Garcia, Stephane; Ferone, Diego; Florio, Tullio; Enjalbert, Alain; Moutardier, Vincent; Schonbrunn, Agnes; Gerard, Corinne; Barlier, Anne; Saveanu, Alexandru

    2014-10-01

    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10 nM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability.

  7. Pancreatic Endocrine Tumors: Expression Profiling Evidences a Role for AKT-mTOR Pathway

    PubMed Central

    Missiaglia, Edoardo; Dalai, Irene; Barbi, Stefano; Beghelli, Stefania; Falconi, Massimo; della Peruta, Marco; Piemonti, Lorenzo; Capurso, Gabriele; Di Florio, Alessia; delle Fave, Gianfranco; Pederzoli, Paolo; Croce, Carlo M.; Scarpa, Aldo

    2010-01-01

    Purpose We investigated the global gene expression in a large panel of pancreatic endocrine tumors (PETs) aimed at identifying new potential targets for therapy and biomarkers to predict patient outcome. Patients and Methods Using a custom microarray, we analyzed 72 primary PETs, seven matched metastases, and 10 normal pancreatic samples. Relevant differentially expressed genes were validated by either quantitative real-time polymerase chain reaction or immunohistochemistry on tissue microarrays. Results Our data showed that: tuberous sclerosis 2 (TSC2) and phosphatase and tensin homolog (PTEN) were downregulated in most of the primary tumors, and their low expression was significantly associated with shorter disease-free and overall survival; somatostatin receptor 2 (SSTR2) was absent or very low in insulinomas compared with nonfunctioning tumors; and expression of fibroblast growth factor 13 (FGF13) gene was significantly associated with the occurrence of liver metastasis and shorter disease-free survival. TSC2 and PTEN are two key inhibitors of the Akt/mammalian target of rapamycin (mTOR) pathway and the specific inhibition of mTOR with rapamycin or RAD001 inhibited cell proliferation of PET cell lines. Conclusion Our results strongly support a role for PI3K/Akt/mTOR pathway in PET, which ties in with the fact that mTOR inhibitors have reached phase III trials in neuroendocrine tumors. The finding of differential SSTR expression raises the potential for SSTR expression to be evaluated as a marker of response to somatostatin analogs. Finally, we identified FGF13 as a new prognostic marker that predicted poorer outcome in patients who were clinically considered free from disease. PMID:19917848

  8. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway.

    PubMed

    Missiaglia, Edoardo; Dalai, Irene; Barbi, Stefano; Beghelli, Stefania; Falconi, Massimo; della Peruta, Marco; Piemonti, Lorenzo; Capurso, Gabriele; Di Florio, Alessia; delle Fave, Gianfranco; Pederzoli, Paolo; Croce, Carlo M; Scarpa, Aldo

    2010-01-10

    We investigated the global gene expression in a large panel of pancreatic endocrine tumors (PETs) aimed at identifying new potential targets for therapy and biomarkers to predict patient outcome. Using a custom microarray, we analyzed 72 primary PETs, seven matched metastases, and 10 normal pancreatic samples. Relevant differentially expressed genes were validated by either quantitative real-time polymerase chain reaction or immunohistochemistry on tissue microarrays. Our data showed that: tuberous sclerosis 2 (TSC2) and phosphatase and tensin homolog (PTEN) were downregulated in most of the primary tumors, and their low expression was significantly associated with shorter disease-free and overall survival; somatostatin receptor 2 (SSTR2) was absent or very low in insulinomas compared with nonfunctioning tumors; and expression of fibroblast growth factor 13 (FGF13) gene was significantly associated with the occurrence of liver metastasis and shorter disease-free survival. TSC2 and PTEN are two key inhibitors of the Akt/mammalian target of rapamycin (mTOR) pathway and the specific inhibition of mTOR with rapamycin or RAD001 inhibited cell proliferation of PET cell lines. Our results strongly support a role for PI3K/Akt/mTOR pathway in PET, which ties in with the fact that mTOR inhibitors have reached phase III trials in neuroendocrine tumors. The finding of differential SSTR expression raises the potential for SSTR expression to be evaluated as a marker of response to somatostatin analogs. Finally, we identified FGF13 as a new prognostic marker that predicted poorer outcome in patients who were clinically considered free from disease.

  9. [Effects of RAGE on Cell Proliferation and Tumor Growth in Pancreatic Cancer].

    PubMed

    Chen, Wei-Wei; Guo, Qiang; Zhang, Zhao-da; Hu, Wei-Ming

    2017-01-01

    To investigate the effect of receptor for advanced glycation end products (RAGE) on cell proliferation and tumor growth in nude mice with pancreatic cancer. PANC-1 cells were transfected with shRNA RAGE -1, -2, -3 to down-regulate the expression of RAGE. Cholecystokinin octopeptide-8 (CCK-8), real-time PCR and Western blot were performed to test the impact of shRNA RAGE on the expressions of mRNAs and proteins of RAGE, matrix metalloproteinase-2 (MMP-2), MMP-9, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and vascular endothelial growth factor (VEGF). Tumor growth and microvessel density in the nude mice implanted with shRNA RAGE transfected PANC-1 cells were observed using immunohistochemistry. The shRNA RAGE -1, -2, -3 transfected cells had lower absorbance values than the controls 24 h after transfection, and the absorbance value reached the lowest at 48 h. The specific shRNA sequences significantly inhibited the expressions of mRNA and protein of RAGE. The mice implanted with shRNA RAGE -2 had lower tumor volume and microvessel density than shRNA RAGE -1, -3. The expressions of mRNAs and proteins of RAGE, MMP-2, NF-κB, MMP-9 and VEGF were lower in the cells transfected with shRNA RAGE -2 compared with shRNA RAGE -1, -3. RAGE is involved in the progression of pancreatic cancerin vitro and in vivo . The RAGE expression could influence the process of tumor angiogenesis.

  10. Systematic evaluation of lung tumor motion using four-dimensional computed tomography.

    PubMed

    Sarudis, Sebastian; Karlsson Hauer, Anna; Nyman, Jan; Bäck, Anna

    2017-04-01

    Respiratory-induced lung tumor motion may decrease robustness and outcome of radiation therapy (RT) if not accounted for. This study provides detailed information on the motion distribution of lung tumors for a group of 126 patients treated with stereotactic body RT. Four-dimensional computed tomography scans were reviewed to assess lung tumor motion. The tumor motion was determined by the center of mass shift based on a rigid registration of the breathing phases containing the largest positional differences in the inferior-superior (IS), left-right (LR), and anterior-posterior (AP) directions. The patients were divided into subgroups depending on tumor diameter (φ < 2.0 cm, 2.0 ≤ φ ≤ 5.0 cm, φ > 5.0 cm) and tumor location within the lung (upper, middle, or lower lobe). The observed motion distributions were evaluated for each group separately to assess the dependence on tumor size and location. For each tumor size, the motion pattern in each direction (IS, LR, and AP) was analyzed for every tumor moving >5 mm. Sinusoidal trigonometric functions were fitted to the measured data using the least mean square method to determine which type of function best describes the motion pattern. Tumor volumes between 1.6 and 52.3 cm(3) were evaluated. Mann-Whitney statistical tests were used for statistical analyses. The mean amplitude for the tumors in this study was 1.5 mm (LR), 2.5 mm (AP), and 6.9 mm (IS) while the maximum amplitude was 11.0 mm (LR), 9.0 mm (AP), and 53.0 mm (IS). In total, 95% of the tumors moved ≤20 mm in the IS direction, ≤3 mm in the LR direction, and ≤6 mm in the AP direction. The observed motion distributions showed no statistically significant correlation with tumor size or location within the lung except for motion in the IS direction, where the mean and maximum amplitudes significantly increased for tumors located in the middle and lower parts of the lung. The motion pattern of a tumor in

  11. Importance of NAB2-STAT6 Fusion in the Diagnosis of Pancreatic Solitary Fibrous Tumor with Hamartoma-Like Features: A Case Report and Review of the Literature

    PubMed Central

    Tanaka, Kei; Kishimoto, Takashi; Ohtsuka, Masayuki; Nakatani, Yukio; Miyazaki, Masaru

    2015-01-01

    We report a case of pancreatic hamartoma-like solitary fibrous tumor which was differentiated from pancreatic hamartoma with the detection of NAB2-STAT6 fusion, a specific mutation for solitary fibrous tumors. A pancreatic well-demarcated solid nodule, 21 × 17 mm, of 82-year-old man was surgically enucleated. Microscopic findings were close to a pancreatic hamartoma that consisted of sparsely distributed pancreatic ducts and acini in heavily collagenized fibrous stroma. Neither islet nor peripheral nerve existed in the tumor. The fibroblastic cells in the stroma were immune-positive for CD34, CD99, and bcl-2. But these expressions were not decisive in the differentiation between solitary fibrous tumor and pancreatic hamartoma, because CD34 was positive for both tumors, and CD99 and bcl-2 expressions were not elucidated in the previous cases of pancreatic hamartomas. Thus, we evaluated NAB2-STAT6 fusion. The fibroblastic cells were positive for STAT6 and sequencing analysis revealed the gene fusion between NAB2 exon 4 and STAT6 exon 2, with which the final diagnos is of solitary fibrous tumor was achieved. In conclusion, detection of NAB2-STAT6 fusion has a great diagnostic value for pancreatic solitary fibrous tumors with hamartoma-like features. PMID:26425382

  12. Toll Like Receptor 2, 4, and 9 Signaling Promotes Autoregulative Tumor Cell Growth and VEGF/PDGF Expression in Human Pancreatic Cancer

    PubMed Central

    Grimmig, Tanja; Moench, Romana; Kreckel, Jennifer; Haack, Stephanie; Rueckert, Felix; Rehder, Roberta; Tripathi, Sudipta; Ribas, Carmen; Chandraker, Anil; Germer, Christoph T.; Gasser, Martin; Waaga-Gasser, Ana Maria

    2016-01-01

    Toll like receptor (TLR) signaling has been suggested to play an important role in the inflammatory microenvironment of solid tumors and through this inflammation-mediated tumor growth. Here, we studied the role of tumor cells in their process of self-maintaining TLR expression independent of inflammatory cells and cytokine milieu for autoregulative tumor growth signaling in pancreatic cancer. We analyzed the expression of TLR2, -4, and -9 in primary human cancers and their impact on tumor growth via induced activation in several established pancreatic cancers. TLR-stimulated pancreatic cancer cells were specifically investigated for activated signaling pathways of VEGF/PDGF and anti-apoptotic Bcl-xL expression as well as tumor cell growth. The primary pancreatic cancers and cell lines expressed TLR2, -4, and -9. TLR-specific stimulation resulted in activated MAP-kinase signaling, most likely via autoregulative stimulation of demonstrated TLR-induced VEGF and PDGF expression. Moreover, TLR activation prompted the expression of Bcl-xL and has been demonstrated for the first time to induce tumor cell proliferation in pancreatic cancer. These findings strongly suggest that pancreatic cancer cells use specific Toll like receptor signaling to promote tumor cell proliferation and emphasize the particular role of TLR2, -4, and -9 in this autoregulative process of tumor cell activation and proliferation in pancreatic cancer. PMID:27941651

  13. The tumor-educated-macrophage increase of malignancy of human pancreatic cancer is prevented by zoledronic acid.

    PubMed

    Hiroshima, Yukihiko; Maawy, Ali; Hassanein, Mohamed K; Menen, Rhiana; Momiyama, Masashi; Murakami, Takashi; Miwa, Shinji; Yamamoto, Mako; Uehara, Fuminari; Yano, Shuya; Mori, Ryutaro; Matsuyama, Ryusei; Chishima, Takashi; Tanaka, Kuniya; Ichikawa, Yasushi; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

    2014-01-01

    We previously defined macrophages harvested from the peritoneal cavity of nude mice with subcutaneous human pancreatic tumors as "tumor-educated-macrophages" (Edu) and macrophages harvested from mice without tumors as "naïve-macrophages" (Naïve), and demonstrated that Edu-macrophages promoted tumor growth and metastasis. In this study, Edu- and Naïve-macrophages were compared for their ability to enhance pancreatic cancer malignancy at the cellular level in vitro and in vivo. The inhibitory efficacy of Zoledronic acid (ZA) on Edu-macrophage-enhanced metastasis was also determined. XPA1 human pancreatic cancer cells in Gelfoam co-cultured with Edu-macrophages proliferated to a greater extent compared to XPA1 cells cultured with Naïve-macrophages (P = 0.014). XPA1 cells exposed to conditioned medium harvested from Edu culture significantly increased proliferation (P = 0.016) and had more migration stimulation capability (P<0.001) compared to cultured cancer cells treated with the conditioned medium from Naïve. The mitotic index of the XPA1 cells, expressing GFP in the nucleus and RFP in the cytoplasm, significantly increased in vivo in the presence of Edu- compared to Naïve-macrophages (P = 0.001). Zoledronic acid (ZA) killed both Edu and Naïve in vitro. Edu promoted tumor growth and metastasis in an orthotopic mouse model of the XPA1 human pancreatic cancer cell line. ZA reduced primary tumor growth (P = 0.006) and prevented metastasis (P = 0.025) promoted by Edu-macrophages. These results indicate that ZA inhibits enhanced primary tumor growth and metastasis of human pancreatic cancer induced by Edu-macrophages.

  14. 4-Methylumbelliferone Suppresses Hyaluronan Synthesis and Tumor Progression in SCID Mice Intra-abdominally Inoculated With Pancreatic Cancer Cells

    PubMed Central

    Nagase, Hayato; Kudo, Daisuke; Suto, Akiko; Yoshida, Eri; Suto, Shinichiro; Negishi, Mika; Kakizaki, Ikuko; Hakamada, Kenichi

    2017-01-01

    Objectives Pancreatic ductal adenocarcinoma contains large amounts of the glycosaminoglycan hyaluronan (HA), which is involved in various physiological processes. Here, we aimed to clarify the anticancer mechanisms of 4-methylumbelliferone (MU), a well-known HA synthesis inhibitor. Methods MIA PaCa-2 human pancreatic cancer cells were used. We evaluated cellular proliferation, migration, and invasion in the presence of MU, exogenous HA, and an anti-CD44 antibody. We also analyzed apoptosis, CD44 expression, and HA-binding ability using flow cytometry. The HA content in tumor tissue was quantified and histopathologically investigated in mice who had been inoculated with cancer cells. Results In vitro, MU inhibited pericellular HA matrix formation; however, HAS3 mRNA was up-regulated. Treatment with 0.5 mM MU suppressed cellular proliferation by 26.4%, migration by 14.7%, and invasion by 22.7%. Moreover, MU also significantly increased apoptosis. CD44 expression and HA-binding ability were not altered by MU. In vivo, MU suppressed HA accumulation in pancreatic tumors and improved survival times in tumor-bearing mice. Conclusions 4-Methylumbelliferone indirectly caused apoptosis in pancreatic cancer cells by inhibiting HA production. 4-Methylumbelliferone may be a promising agent in the treatment of pancreatic cancer. PMID:27846148

  15. Tumor Cell-derived MMP-3 Orchestrates Rac1b and Tissue Alterations that Promote Pancreatic Adenocarcinoma

    PubMed Central

    Mehner, Christine; Miller, Erin; Khauv, Davitte; Nassar, Aziza; Oberg, Ann L.; Bamlet, William R.; Zhang, Lizhi; Waldmann, Jens; Radisky, Evette S.; Crawford, Howard C.; Radisky, Derek C.

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDA) arises at the convergence of genetic alterations in KRAS with a fostering microenvironment shaped by immune cell influx and fibrotic changes; identification of the earliest tumorigenic molecular mediators evokes the proverbial chicken and egg problem. Matrix metalloproteinases (MMPs) are key drivers of tumor progression that originate primarily from stromal cells activated by the developing tumor. Here matrix metalloproteinase-3 (MMP3), known to be expressed in PDA, was found to be associated with expression of Rac1b, a tumorigenic splice isoform of Rac1, in all stages of pancreatic cancer. Using a large cohort of human PDA tissue biopsies specimens, both MMP3 and Rac1b are expressed in PDA cells, that the expression levels of the two markers are highly correlated, and that the subcellular distribution of Rac1b in PDA is significantly associated with patient outcome. Using transgenic mouse models, co-expression of MMP3 with activated KRAS in pancreatic acinar cells stimulates metaplasia and immune cell infiltration, priming the stromal microenvironment for early tumor development. Finally, exposure of cultured pancreatic cancer cells to recombinant MMP3 stimulates expression of Rac1b, increases cellular invasiveness, and activation of tumorigenic transcriptional profiles. Implications MMP3 acts as a co-conspirator of oncogenic KRAS in pancreatic cancer tumorigenesis and progression, both through Rac1b-mediated phenotypic control of pancreatic cancer cells themselves, and by giving rise to the tumorigenic microenvironment; these findings also point to inhibition of this pathway as a potential therapeutic strategy for pancreatic cancer. PMID:24850902

  16. Computed tomography-guided percutaneous core needle biopsy in pancreatic tumor diagnosis.

    PubMed

    Tyng, Chiang J; Almeida, Maria Fernanda A; Barbosa, Paula N V; Bitencourt, Almir G V; Berg, José Augusto A G; Maciel, Macello S; Coimbra, Felipe J F; Schiavon, Luiz Henrique O; Begnami, Maria Dirlei; Guimarães, Marcos D; Zurstrassen, Charles E; Chojniak, Rubens

    2015-03-28

    To evaluate the techniques, results, and complications related to computed tomography (CT)-guided percutaneous core needle biopsies of solid pancreatic lesions. CT-guided percutaneous biopsies of solid pancreatic lesions performed at a cancer reference center between January 2012 and September 2013 were retrospectively analyzed. Biopsy material was collected with a 16-20 G Tru-Core needle (10-15 cm; Angiotech, Vancouver, CA) using a coaxial system and automatic biopsy gun. When direct access to the lesion was not possible, indirect (transgastric or transhepatic) access or hydrodissection and/or pneumodissection maneuvers were used. Characteristics of the patients, lesions, procedures, and histologic results were recorded using a standardized form. A total of 103 procedures included in the study were performed on patients with a mean age of 64.8 year (range: 39-94 year). The mean size of the pancreatic lesions was 45.5 mm (range: 15-195 mm). Most (75/103, 72.8%) procedures were performed via direct access, though hydrodissection and/or pneumodissection were used in 22.2% (23/103) of cases and indirect transhepatic or transgastric access was used in 4.8% (5/103) of cases. Histologic analysis was performed on all biopsies, and diagnoses were conclusive in 98.1% (101/103) of cases, confirming 3.9% (4/103) of tumors were benign and 94.2% (97/103) were malignant; results were atypical in 1.9% (2/103) of cases, requiring a repeat biopsy to diagnose a neuroendocrine tumor, and surgical resection to confirm a primary adenocarcinoma. Only mild/moderate complications were observed in 9/103 patients (8.7%), and they were more commonly associated with biopsies of lesions located in the head/uncinate process (n = 8), than of those located in the body/tail (n = 1) of the pancreas, but this difference was not significant. CT-guided biopsy of a pancreatic lesion is a safe procedure with a high success rate, and is an excellent option for minimally invasive diagnosis.

  17. Computed tomography-guided percutaneous core needle biopsy in pancreatic tumor diagnosis

    PubMed Central

    Tyng, Chiang J; Almeida, Maria Fernanda A; Barbosa, Paula NV; Bitencourt, Almir GV; Berg, José Augusto AG; Maciel, Macello S; Coimbra, Felipe JF; Schiavon, Luiz Henrique O; Begnami, Maria Dirlei; Guimarães, Marcos D; Zurstrassen, Charles E; Chojniak, Rubens

    2015-01-01

    AIM: To evaluate the techniques, results, and complications related to computed tomography (CT)-guided percutaneous core needle biopsies of solid pancreatic lesions. METHODS: CT-guided percutaneous biopsies of solid pancreatic lesions performed at a cancer reference center between January 2012 and September 2013 were retrospectively analyzed. Biopsy material was collected with a 16-20 G Tru-Core needle (10-15 cm; Angiotech, Vancouver, CA) using a coaxial system and automatic biopsy gun. When direct access to the lesion was not possible, indirect (transgastric or transhepatic) access or hydrodissection and/or pneumodissection maneuvers were used. Characteristics of the patients, lesions, procedures, and histologic results were recorded using a standardized form. RESULTS: A total of 103 procedures included in the study were performed on patients with a mean age of 64.8 year (range: 39-94 year). The mean size of the pancreatic lesions was 45.5 mm (range: 15-195 mm). Most (75/103, 72.8%) procedures were performed via direct access, though hydrodissection and/or pneumodissection were used in 22.2% (23/103) of cases and indirect transhepatic or transgastric access was used in 4.8% (5/103) of cases. Histologic analysis was performed on all biopsies, and diagnoses were conclusive in 98.1% (101/103) of cases, confirming 3.9% (4/103) of tumors were benign and 94.2% (97/103) were malignant; results were atypical in 1.9% (2/103) of cases, requiring a repeat biopsy to diagnose a neuroendocrine tumor, and surgical resection to confirm a primary adenocarcinoma. Only mild/moderate complications were observed in 9/103 patients (8.7%), and they were more commonly associated with biopsies of lesions located in the head/uncinate process (n = 8), than of those located in the body/tail (n = 1) of the pancreas, but this difference was not significant. CONCLUSION: CT-guided biopsy of a pancreatic lesion is a safe procedure with a high success rate, and is an excellent option for minimally

  18. Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer

    PubMed Central

    Liu, Xiangsheng; Lin, Paulina; Perrett, Ian; Lin, Joshua; Liao, Yu-Pei; Chang, Chong Hyun; Jiang, Jinhong; Wu, Nanping; Donahue, Timothy; Wainberg, Zev; Nel, Andre E.; Meng, Huan

    2017-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal; however, some improvement in overall survival has been achieved with the introduction of nanocarriers that deliver irinotecan or paclitaxel. Although it is generally assumed that nanocarriers rely principally on abnormal leaky vasculature for tumor access, a transcytosis transport pathway that is regulated by neuropilin-1 (NRP-1) has recently been reported. NRP-1–mediated transport can be triggered by the cyclic tumor-penetrating peptide iRGD. In a KRAS-induced orthotopic PDAC model, coadministration of iRGD enhanced the uptake of an irinotecan-loaded silicasome carrier that comprises lipid bilayer–coated mesoporous silica nanoparticles (MSNPs); this uptake resulted in enhanced survival and markedly reduced metastasis. Further, ultrastructural imaging of the treated tumors revealed that iRGD coadministration induced a vesicular transport pathway that carried Au-labeled silicacomes from the blood vessel lumen to a perinuclear site within cancer cells. iRGD-mediated enhancement of silicasome uptake was also observed in patient-derived xenografts, commensurate with the level of NRP-1 expression on tumor blood vessels. These results demonstrate that iRGD enhances the efficacy of irinotecan-loaded silicasome–based therapy and may be a suitable adjuvant in nanoparticle-based treatments for PDAC. PMID:28414297

  19. Doublecortin-like kinase 1 is elevated serologically in pancreatic ductal adenocarcinoma and widely expressed on circulating tumor cells.

    PubMed

    Qu, Dongfeng; Johnson, Jeremy; Chandrakesan, Parthasarathy; Weygant, Nathaniel; May, Randal; Aiello, Nicole; Rhim, Andrew; Zhao, Lichao; Zheng, Wei; Lightfoot, Stanley; Pant, Shubham; Irvan, Jeremy; Postier, Russell; Hocker, James; Hanas, Jay S; Ali, Naushad; Sureban, Sripathi M; An, Guangyu; Schlosser, Michael J; Stanger, Ben; Houchen, Courtney W

    2015-01-01

    Doublecortin-like kinase 1 (DCLK1) is a putative pancreatic stem cell marker and is upregulated in pancreatic cancer, colorectal cancer, and many other solid tumors. It marks tumor stem cells in mouse models of intestinal neoplasia. Here we sought to determine whether DCLK1 protein can be detected in the bloodstream and if its levels in archived serum samples could be quantitatively assessed in pancreatic cancer patients. DCLK1 specific ELISA, western blotting, and immunohistochemical analyses were used to determine expression levels in the serum and staining intensity in archived tumor tissues of pancreatic ductal adenocarcinoma (PDAC) patients and in pancreatic cancer mouse models. DCLK1 levels in the serum were elevated in early stages of PDAC (stages I and II) compared to healthy volunteers (normal controls). No differences were observed between stages III/IV and normal controls. In resected surgical tissues, DCLK1 expression intensity in the stromal cells was significantly higher than that observed in tumor epithelial cells. Circulating tumor cells were isolated from KPCY mice and approximately 52% of these cells were positive for Dclk1 staining. Dclk1 levels in the serum of KPC mice were also elevated. We have previously demonstrated that DCLK1 plays a potential role in regulating epithelial mesenchymal transition (EMT). Given the increasingly recognized role of EMT derived stem cells in cancer progression and metastasis, we hypothesize that DCLK1 may contribute to the metastatic process. Taken together, our results suggest that DCLK1 serum levels and DCLK1 positive circulating tumor cells should be further assessed for their potential diagnostic and prognostic significance.

  20. Doublecortin-Like Kinase 1 Is Elevated Serologically in Pancreatic Ductal Adenocarcinoma and Widely Expressed on Circulating Tumor Cells

    PubMed Central

    Weygant, Nathaniel; May, Randal; Aiello, Nicole; Rhim, Andrew; Zhao, Lichao; Zheng, Wei; Lightfoot, Stanley; Pant, Shubham; Irvan, Jeremy; Postier, Russell; Hocker, James; Hanas, Jay S.; Ali, Naushad; Sureban, Sripathi M.; An, Guangyu; Schlosser, Michael J.; Stanger, Ben; Houchen, Courtney W.

    2015-01-01

    Doublecortin-like kinase 1 (DCLK1) is a putative pancreatic stem cell marker and is upregulated in pancreatic cancer, colorectal cancer, and many other solid tumors. It marks tumor stem cells in mouse models of intestinal neoplasia. Here we sought to determine whether DCLK1 protein can be detected in the bloodstream and if its levels in archived serum samples could be quantitatively assessed in pancreatic cancer patients. DCLK1 specific ELISA, western blotting, and immunohistochemical analyses were used to determine expression levels in the serum and staining intensity in archived tumor tissues of pancreatic ductal adenocarcinoma (PDAC) patients and in pancreatic cancer mouse models. DCLK1 levels in the serum were elevated in early stages of PDAC (stages I and II) compared to healthy volunteers (normal controls). No differences were observed between stages III/IV and normal controls. In resected surgical tissues, DCLK1 expression intensity in the stromal cells was significantly higher than that observed in tumor epithelial cells. Circulating tumor cells were isolated from KPCY mice and approximately 52% of these cells were positive for Dclk1 staining. Dclk1 levels in the serum of KPC mice were also elevated. We have previously demonstrated that DCLK1 plays a potential role in regulating epithelial mesenchymal transition (EMT). Given the increasingly recognized role of EMT derived stem cells in cancer progression and metastasis, we hypothesize that DCLK1 may contribute to the metastatic process. Taken together, our results suggest that DCLK1 serum levels and DCLK1 positive circulating tumor cells should be further assessed for their potential diagnostic and prognostic significance. PMID:25723399

  1. Inflammatory myofibroblastic tumor of the distal bile duct associated with lymphoplasmacytic sclerosing pancreatitis. Case report and review of the literature.

    PubMed

    Martín Malagón, Antonio; López-Tomassetti Fernández, Eudaldo; Arteaga González, Iván; Carrillo Pallarés, Angel; Díaz Luis, Hermogenes

    2006-01-01

    Inflammatory myofibroblastic tumor (IMT) or inflammatory pseudotumor has been described in various organs such as the liver, intestinal tract, spleen, kidney, bladder, lung, peritoneum and heart. However, its appearance in the periampullary region is uncommon and has rarely been reported in the literature. It is characterized histologically by myofibroblastic cell proliferation together with a mixed inflammatory infiltrate that clinically and radiologically mimics a malignant tumor. We report a case of IMT located in the distal common bile duct of a 51-year-old woman. She underwent Whipple resection with the initial diagnosis of cholangiocarcinoma; the pathologic diagnosis of the tumor was IMT of the distal bile duct associated with lymphoplasmacytic sclerosing pancreatitis. Referring to previously reported cases, suspected diagnosis of a malignant tumor made surgical excision the primary choice for symptom relief and in order to obtain a definitive diagnosis. IMT relationship with lymphoplasmacytic sclerosing pancreatitis is discussed.

  2. RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors

    PubMed Central

    Wu, Yonghe; Tedesco, Lucas; Lucia, Kristin; Schlitter, Anna M.; Garcia, Jose Monteserin; Esposito, Irene; Auernhammer, Christoph J.; Theodoropoulou, Marily; Arzt, Eduardo; Renner, Ulrich; Stalla, Günter K.

    2016-01-01

    The factors triggering pancreatic neuroendocrine tumor (PanNET) progression are largely unknown. Here we investigated the role and mechanisms of the sumoylation enhancing protein RSUME in PanNET tumorigenesis. Immunohistochemical studies showed that RSUME is strongly expressed in normal human pancreas, in particular in β-cells. RSUME expression is reduced in insulinomas and is nearly absent in other types of PanNETs suggesting a role in PanNET tumorigenesis. In human pancreatic neuroendocrine BON1 cells, RSUME stimulates hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A), which are key components of tumor neovascularisation. In contrast, RSUME suppresses nuclear factor-κB (NF-κB) and its target interleukin-8 (IL-8). Correspondingly, PanNET cells with RSUME knockdown showed decreased HIF-1α activity and increased NF-κB and IL-8 production leading to a moderate reduction of VEGF-A release as reduced HIF-1α/VEGF-A production is partly compensated by NF-κB/IL-8-induced VEGF-A. Notably, RSUME stabilizes the tumor suppressor PTEN, which is frequently lost in PanNETs and whose absence is associated with metastasis formation. In vivo orthotopic transplantation of PanNET cells with or without RSUME expression into nude mice showed that PanNETs without RSUME have reduced PTEN expression, grow faster and form multiple liver metastases. In sum, RSUME differentially regulates key components of PanNET formation suggesting that the observed loss of RSUME in advanced PanNETs is critically involved in PanNET tumorigenesis, particularly in metastasis formation. PMID:27506944

  3. Targeting Focal Adhesion Kinase and Resistance to mTOR Inhibition in Pancreatic Neuroendocrine Tumors

    PubMed Central

    François, Rony A.; Maeng, Kyungah; Nawab, Akbar; Kaye, Frederic J.; Hochwald, Steven N.; Zajac-Kaye, Maria

    2015-01-01

    Background: Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling. Methods: We characterized the activation of FAK in PanNETs using immunohistochemistry and Western blot analysis and tested the FAK inhibitor PF-04554878 in human PanNET cells in vitro and in vivo (at least three mice per group). In addition, we evaluated the effect of combined FAK and mTOR inhibition on PanNET viability and apoptosis. All statistical tests were two-sided. Results: We found that FAK is overexpressed and hyperphosphorylated in human PanNETs and that PF-04554878 strongly inhibited FAK (Tyr397) autophosphorylation in a dose-dependent manner. We found that PF-04554878 inhibited cell proliferation and clonogenicity and induced apoptosis in PanNET cells. Moreover, oral administration of PF-04554878 statistically significantly reduced tumor growth in a patient-derived xenograft model of PanNET (P = .02) and in a human PanNET xenograft model of peritoneal carcinomatosis (P = .03). Importantly, PF-04554878 synergized with the mTOR inhibitor everolimus by preventing feedback AKT activation. Conclusions: We demonstrate for the first time that FAK is overexpressed in PanNETs and that inhibition of FAK activity induces apoptosis and inhibits PanNET proliferation. We found that the novel FAK inhibitor PF-04554878 synergizes with everolimus, a US Food and Drug Administration–approved agent for PanNETs. Our findings warrant the clinical investigation of combined FAK and mTOR inhibition in PanNETs. PMID:25971297

  4. Broncho-biliary fistula secondary to biliary obstruction and lung abscess in a patient with pancreatic neuro-endocrine tumor.

    PubMed

    Panda, Dipanjan; Aggarwal, Mayank; Yadav, Vikas; Kumar, Sachin; Mukund, Amar; Baghmar, Saphalta

    2016-06-01

    We present a case report of broncho-biliary fistula that developed due to the blockage of biliary stent placed during the management of pancreatic neuroendocrine tumor (pNET); diagnosed on high clinical suspicion, percutaneous cholangiogram and contrast enhanced computed tomography (CECT); and successfully treated with percutaneous transhepatic biliary drainage (PTBD).

  5. Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer.

    PubMed

    Yao, Jun; Zhang, Lu-Lin; Huang, Xu-Mei; Li, Wen-Yao; Gao, She-Gan

    2017-06-07

    To detect the expression of pleiotrophin (PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion (PNI). An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis. The expression rates of PTN and N-syndecan proteins were 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI (P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites (P = 0.009), liver metastasis (P = 0.035), and decreased survival time (P = 0.022). N-syndecan expression was significantly associated with tumor size (P = 0.025), but not with survival time (P = 0.539). High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer.

  6. Tumor-Specific Fluorescent Antibody Imaging Enables Accurate Staging Laparoscopy in an Orthotopic Model of Pancreatic Cancer

    PubMed Central

    Cao, Hop S Tran; Kaushal, Sharmeela; Metildi, Cristina A; Menen, Rhiana S; Lee, Claudia; Snyder, Cynthia S; Messer, Karen; Pu, Minya; Luiken, George A; Talamini, Mark A; Hoffman, Robert M; Bouvet, Michael

    2014-01-01

    Background/Aims Laparoscopy is important in staging pancreatic cancer, but false negatives remain problematic. Making tumors fluorescent has the potential to improve the accuracy of staging laparoscopy. Methodology Orthotopic and carcinomatosis models of pancreatic cancer were established with BxPC-3 human pancreatic cancer cells in nude mice. Alexa488-anti-CEA conjugates were injected via tail vein 24 hours prior to laparoscopy. Mice were examined under bright field laparoscopic (BL) and fluorescence laparoscopic (FL) modes. Outcomes measured included time to identification of primary tumor for the orthotopic model and number of metastases identified within 2 minutes for the carcinomatosis model. Results FL enabled more rapid and accurate identification and localization of primary tumors and metastases than BL. Using BL took statistically significantly longer time than FL. More metastatic lesions were detected and localized under FL compared to BL and with greater accuracy, with sensitivities of 96% vs. 40%, respectively, when compared to control. FL was sensitive enough to detect metastatic lesions <1mm. Conclusions The use of fluorescence laparoscopy with tumors labeled with fluorophore-conjugated anti-CEA antibody permits rapid detection and accurate localization of primary and metastatic pancreatic cancer in an orthotopic model. The results of the present report demonstrate the future clinical potential of fluorescence laparoscopy. PMID:22369743

  7. In vivo magnetic resonance imaging of pancreatic tumors using iron oxide nanoworms targeted with PTR86 peptide.

    PubMed

    Ahmadi, Yasaman; Kostenich, Genady; Oron-Herman, Mor; Wadsak, Wolfgang; Mitterhauser, Markus; Orenstein, Arie; Mirzaei, Siroos; Knoll, Peter

    2017-07-06

    To cut the high mortality rate of malignant disease such as pancreatic cancer, development of newly diagnostic probes for early stage detection of tumor lesions is required. Multimodal imaging nanoprobes allowing targeted and real time functional/anatomical imaging of tumors meet the demands. For this purpose, a MRI/optical dual-modality probe based on biodegradable magnetic iron oxide nanoworms has been developed. The cross-linked surface of nanoworms were anchored to fluorescent dyes and to FITC.PTR86; a novel synthetic peptide with high affinity towards somatostatin receptors. Combination of various in vitro techniques including Prussian blue staining, fluorescent microscopy and fluorescence activated cell sorting (FACS) have been performed to explore the interaction of developed nanoprobe with pancreatic tumor cell lines. Together with in vivo studies in a xenograft mouse model of human pancreatic adenocarcinoma and ex vivo investigations, the results show the efficient imaging and targeting of pancreatic tumors by our newly developed nanosystem using both MRI and optical imaging modalities. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Expression of gremlin 1 correlates with increased angiogenesis and progression-free survival in patients with pancreatic neuroendocrine tumors.

    PubMed

    Chen, Ming-Huang; Yeh, Yi-Chen; Shyr, Yi-Ming; Jan, Yi-Hua; Chao, Yee; Li, Chung-Pin; Wang, Shin-E; Tzeng, Cheng-Hwai; Chang, Peter Mu-Hsin; Liu, Chun-Yu; Chen, Ming-Han; Hsiao, Michael; Huang, Chi-Ying F

    2013-01-01

    Gremlin 1 (GREM1) is a bone morphogenetic protein antagonist and a novel proangiogenic factor. Our aim was to evaluate the prognostic value of GREM1 expression and GREM1-related factors in tumor-associated angiogenesis in pancreatic neuroendocrine tumors (NETs). The immunohistochemical expression of GREM1 and microvessel density (MVD) were examined in 35 patients with pancreatic NETs and then compared with other clinicopathologic characteristics, including the World Health Organization classification. The presence of expression of GREM1 (p = 0.016) and high MVD (p = 0.020) were significant and favorable prognostic factors. Moreover, GREM1 expression was significantly associated with high MVD (p = 0.011). MVD was significantly higher in well-differentiated NETs than in well-differentiated or poorly differentiated neuroendocrine carcinomas (p < 0.001). GREM1 expression was correlated with tumor-associated angiogenesis and was found to be a novel prognostic marker in pancreatic NETS. Our data support a tumor suppressor role of GREM1 in pancreatic NETs.

  9. A biomechanical approach for in vivo lung tumor motion prediction during external beam radiation therapy

    NASA Astrophysics Data System (ADS)

    Karami, Elham; Gaede, Stewart; Lee, Ting-Yim; Samani, Abbas

    2015-03-01

    Lung Cancer is the leading cause of cancer death in both men and women. Among various treatment methods currently being used in the clinic, External Beam Radiation Therapy (EBRT) is used widely not only as the primary treatment method, but also in combination with chemotherapy and surgery. However, this method may lack desirable dosimetric accuracy because of respiration induced tumor motion. Recently, biomechanical modeling of the respiratory system has become a popular approach for tumor motion prediction and compensation. This approach requires reasonably accurate data pertaining to thoracic pressure variation, diaphragm position and biomechanical properties of the lung tissue in order to predict the lung tissue deformation and tumor motion. In this paper, we present preliminary results of an in vivo study obtained from a Finite Element Model (FEM) of the lung developed to predict tumor motion during respiration.

  10. Image-Guided Radiofrequency Ablation of a Pancreatic Tumor with a New Triple Spiral-Shaped Electrode

    SciTech Connect

    Thanos, Loukas; Poulou, Loukia S.; Mailli, Lito; Pomoni, Maria; Kelekis, Dimitrios A.

    2010-02-15

    Image-guided, minimally invasive treatment modalities have become an area of considerable interest and research during the last few years for the treatment of primary and secondary liver tumors. We report our experience with an unresectable pancreatic tumor, treated with application of radiofrequency ablation under CT guidance that even though a complication occurred during the procedure, had excellent results on follow-up CT scans.

  11. Pre-clinical evaluation of a novel CEA-targeting near-infrared fluorescent tracer delineating colorectal and pancreatic tumors

    PubMed Central

    Boonstra, Martin C.; Tolner, Berend; Schaafsma, Boudewijn E.; Boogerd, Leonora S.F.; Prevoo, Hendrica A.J.M; Bhavsar, Guarav; Kuppen, Peter J.K.; Sier, Cornelis F.M.; Bonsing, Bert A.; Frangioni, John V.; van de Velde, Cornelis J.H.; Chester, Kerry A.; Vahrmeijer, Alexander L.

    2016-01-01

    Surgery is the cornerstone of oncologic therapy with curative intent. However, identification of tumor cells in the resection margins is difficult, resulting in non-radical resections, increased cancer recurrence and subsequent decreased patient survival. Novel imaging techniques that aid in demarcating tumor margins during surgery are needed. Overexpression of carcinoembryonic antigen (CEA) is found in the majority of gastro-intestinal carcinomas, including colorectal and pancreas. We developed ssSM3E/800CW, a novel CEA-targeted near-infrared fluorescent (NIRF) tracer, based on a disulphide stabilized single-chain antibody fragment (ssScFv), to visualize colorectal and pancreatic tumors in a clinically translatable setting. The applicability of the tracer was tested for cell and tissue binding characteristics and dosing using immunohistochemistry, flow cytometry, cell-based plate assays and orthotopic colorectal (HT-29, well differentiated) and pancreatic (BXPC-3, poorly differentiated) xenogeneic human-mouse models. NIRF signals were visualized using the clinically compatible FLARE™ imaging system. Calculated clinically relevant doses of ssSM3E/800CW selectively accumulated in colorectal and pancreatic tumors/cells, with highest tumor-to-background ratios of 5.1±0.6 at 72 h post-injection, which proved suitable for intra-operative detection and delineation of tumor boarders and small (residual) tumor-nodules in mice, between 8 h and 96 h post-injection. Ex vivo fluorescence imaging and pathologic examination confirmed tumor-specificity and the distribution of the tracer. Our results indicate that ssSM3E/800CW shows promise as a diagnostic tool to recognize colorectal and pancreatic cancers for fluorescent-guided surgery applications. If successful translated clinically, this tracer could help improve the completeness of surgery and thus survival. PMID:25895046

  12. Microscopic venous invasion in patients with pancreatic neuroendocrine tumor as a potential predictor of postoperative recurrence.

    PubMed

    Nanno, Yoshihide; Toyama, Hirochika; Otani, Kyoko; Asari, Sadaki; Goto, Tadahiro; Terai, Sachio; Ajiki, Tetsuo; Zen, Yoh; Fukumoto, Takumi; Ku, Yonson

    2016-01-01

    Microscopic venous and lymphatic invasion is a known prognostic factor for various cancers, but its prognostic relevance for pancreatic neuroendocrine tumors (PNETs) is unclear. Thirty-two consecutive patients with PNET who had complete resection were included in this study. Venous and lymphatic invasion was identified on elastic tissue or immunohistochemical staining, and correlated with other clinicopathological factors, including recurrence-free survival. Venous and lymphatic invasion was identified in nine (28%) and three (9%) patients, respectively. Tumors with venous invasion were of significantly larger size, higher Ki-67 index, and higher mitotic counts. Patients with venous invasion showed significantly worse prognosis than those without venous invasion (P = 0.001). Five of nine patients (56%) with venous invasion had tumor recurrence, while a relapse was found in one case in patients without venous invasion (n = 23). Lymphatic invasion was not correlated with any other clinicopathological parameters including lymph node metastasis and recurrence-free survival. Predictive factors for recurrence in univariate analysis included microscopic venous invasion, tumor size ≥ 20 mm, non-functionality, and WHO grades. In multivariate analysis where WHO grades and microscopic venous invasion were applied, venous invasion remained a significant predictor of poor recurrence-free survival (P = 0.021). Microscopic venous invasion may serve as a predictive factor for tumor recurrence in patients with resectable PNET. The combination of WHO grades and microscopic venous invasion may assist in the stratification of the patients for risk of tumor recurrence. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  13. Fucosyltransferase activities in human pancreatic tissue: comparative study between cancer tissues and established tumoral cell lines.

    PubMed

    Mas, E; Pasqualini, E; Caillol, N; El Battari, A; Crotte, C; Lombardo, D; Sadoulet, M O

    1998-06-01

    Human pancreatic cancer is characterized by an alteration in fucose-containing surface blood group antigens such as H antigen, Lewis b, Lewis y, and sialyl-Lewis. These carbohydrate determinants can be synthesized by sequential action of alpha(2,3) sialyltransferases or alpha(1,2) fucosyltransferases (Fuc-T) and alpha(1,3/1,4) fucosyltransferases on (poly)N-acetyllactosamine chains. Therefore, the expression and the function of seven fucosyltransferases were investigated in normal and cancer pancreatic tissues and in four pancreatic carcinoma cell lines. Transcripts of FUT1, FUT2, FUT3, FUT4, FUT5, and FUT7 were detected by RT-PCR in carcinoma cell lines as well as in normal and tumoral tissues. Interestingly, the FUT6 message was only detected in tumoral tissues. Analysis of the acceptor substrate specificity for fucosyltransferases indicated that alpha(1,2) Fuc-T, alpha(1,3) Fuc-T, and alpha(1,4) Fuc-T were expressed in microsome preparations of all tissues as demonstrated by fucose incorporation into phenyl beta-d-galactoside, 2'-fucosyllactose, N-acetyllactosamine, 3'-sialyl-N-acetyllactosamine, and lacto-N-biose. However, these fucosyltransferase activities varied between tissues. A substantial decrease of alpha(1,2) Fuc-T activity was observed in tumoral tissues and cell lines compared to normal tissues. Conversely, the activity of alpha(1,4) Fuc-T, which generates Lewis a and sialyl-Lewis a structures, and that of alpha(1,3) Fuc-T, able to generate a lactodifucotetraose structure, were very important in SOJ-6 and BxPC-3 cell lines. These increases correlated with an enhanced expression of Lewis a, sialyl-Lewis a, and Lewis y on the cell surface. The activity of alpha(1,3) Fuc-T, which participates in the synthesis of the sialyl-Lewis x structure, was not significantly modified in cell lines compared to normal tissues. However, the sialyl-Lewis x antigen was expressed preferentially on the surface of SOJ-6 and BxPC-3 cell lines but was not detected on Panc-1

  14. Multimodality Management of "Borderline Resectable" Pancreatic Neuroendocrine Tumors: Report of a Single-Institution Experience.

    PubMed

    Ambe, Chenwi M; Nguyen, Phuong; Centeno, Barbara A; Choi, Junsung; Strosberg, Jonathan; Kvols, Larry; Hodul, Pamela; Hoffe, Sarah; Malafa, Mokenge P

    2017-01-01

    Pancreatic neuroendocrine tumors (PanNETs) constitute approximately 3% of pancreatic neoplasms. Like patients with pancreatic ductal adenocarcinoma (PDAC), some of these patients present with "borderline resectable disease." For these patients, an optimal treatment approach is lacking. We report our institution's experience with borderline resectable PanNETs using multimodality treatment. We identified patients with borderline resectable PanNETs who had received neoadjuvant therapy at our institution between 2000 and 2013. The definition of borderline resectability was based on National Comprehensive Cancer Network criteria for PDAC. Neoadjuvant regimen, radiographic response, pathologic response, surgical margins, nodal retrieval, number of positive nodes, and recurrence were documented. Statistics were descriptive. Of 112 patients who underwent surgical resection for PanNETs during the study period, 23 received neoadjuvant therapy, 6 of whom met all inclusion criteria and had borderline resectable disease. These 6 patients received at least 1 cycle of temozolomide and capecitabine, with 3 also receiving radiation. All had radiographic evidence of treatment response. Four (67%) had negative-margin resections. Four patients had histologic evidence of a moderate response. Follow-up (3.0-4.3 years) indicated that all patients were alive, with 5/6 free of disease (1 patient with metastatic disease still on treatment without progression). A multimodality treatment strategy (neoadjuvant temozolomide and capecitabine ± radiation) can be successfully applied to patients with PanNETs who meet NCCN borderline resectable criteria for PDAC. To our knowledge, this is the first report of the use of a multimodality protocol in the treatment of patients with borderline resectable PanNETs.

  15. Comparison of Liver Tumor Motion With and Without Abdominal Compression Using Cine-Magnetic Resonance Imaging

    SciTech Connect

    Eccles, Cynthia L.; Patel, Ritesh; Simeonov, Anna K.; Lockwood, Gina; Haider, Masoom; Dawson, Laura A.

    2011-02-01

    Purpose: Abdominal compression (AC) can be used to reduce respiratory liver motion in patients undergoing liver stereotactic body radiotherapy. The purpose of the present study was to measure the changes in three-dimensional liver tumor motion with and without compression using cine-magnetic resonance imaging. Patients and Methods: A total of 60 patients treated as a part of an institutional research ethics board-approved liver stereotactic body radiotherapy protocol underwent cine T2-weighted magnetic resonance imaging through the tumor centroid in the coronal and sagittal planes. A total of 240 cine-magnetic resonance imaging sequences acquired at one to three images each second for 30-60 s were evaluated using an in-house-developed template matching tool (based on the coefficient correlation) to measure the magnitude of the tumor motion. The average tumor edge displacements were used to determine the magnitude of changes in the caudal-cranial (CC) and anteroposterior (AP) directions, with and without AC. Results: The mean tumor motion without AC of 11.7 mm (range, 4.8-23.3) in the CC direction was reduced to 9.4 mm (range, 1.6-23.4) with AC. The tumor motion was reduced in both directions (CC and AP) in 52% of the patients and in a single direction (CC or AP) in 90% of the patients. The mean decrease in tumor motion with AC was 2.3 and 0.6 mm in the CC and AP direction, respectively. Increased motion occurred in one or more directions in 28% of patients. Clinically significant (>3 mm) decreases were observed in 40% and increases in <2% of patients in the CC direction. Conclusion: AC can significantly reduce three-dimensional liver tumor motion in most patients, although the magnitude of the reduction was smaller than previously reported.

  16. Pancreatic solitary fibrous tumor in a toddler managed by pancreaticoduodenectomy: a case report and review of the literature

    PubMed Central

    Sheng, Qingfeng; Xu, Weijue; Liu, Jiangbin; Shen, Baiyong; Deng, Xiaxing; Wu, Yibo; Wu, Wei; Yu, Shenghua; Wang, Xueli; Lv, Zhibao

    2017-01-01

    Solitary fibrous tumor (SFT) of the pancreas is rare, with 15 adult cases reported in the English literature. We described a 14-month-old boy who presented with obstructive jaundice. Dominantly elevated serum CA19-9 was detected. Imaging studies revealed a well-circumscribed, solid mass in the pancreatic head. A pancreaticoduodenectomy (child procedure) was performed using Shen’s anastomosis technique. After resection of the tumor, liver function and serum tumor markers normalized and clinical signs receded. The boy was disease free after a follow-up of 12 months. Histological examination showed the tumor consisted of “patternless pattern” arranged spindle tumor cells and keloid-like hyalinized collagen. Immunohistochemical staining was positive for CD34 and vimentin. Mutation analysis of CTNNB1 was negative. To the best of our knowledge, our patient was the first case of pancreatic SFT in a pediatric population. SFT should be considered in differential diagnosis when confronted with a pancreatic tumor in children. Complete resection should be meticulously pursued. PMID:28392706

  17. Frequency filtering based analysis on the cardiac induced lung tumor motion and its impact on the radiotherapy management.

    PubMed

    Chen, Ting; Qin, Songbing; Xu, Xiaoting; Jabbour, Salma K; Haffty, Bruce G; Yue, Ning J

    2014-09-01

    Lung tumor motion may be impacted by heartbeat in addition to respiration. This study seeks to quantitatively analyze heart-motion-induced tumor motion and to evaluate its impact on lung cancer radiotherapy. Fluoroscopy images were acquired for 30 lung cancer patients. Tumor, diaphragm, and heart were delineated on selected fluoroscopy frames, and their motion was tracked and converted into temporal signals based on deformable registration propagation. The clinical relevance of heart impact was evaluated using the dose volumetric histogram of the redefined target volumes. Correlation was found between tumor and cardiac motion for 23 patients. The heart-induced motion amplitude ranged from 0.2 to 2.6 mm. The ratio between heart-induced tumor motion and the tumor motion was inversely proportional to the amplitude of overall tumor motion. When the heart motion impact was integrated, there was an average 9% increase in internal target volumes for 17 patients. Dose coverage decrease was observed on redefined planning target volume in simulated SBRT plans. The tumor motion of thoracic cancer patients is influenced by both heart and respiratory motion. The cardiac impact is relatively more significant for tumor with less motion, which may lead to clinically significant uncertainty in radiotherapy for some patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Distribution and clinical significance of Th17 cells in the tumor microenvironment and peripheral blood of pancreatic cancer patients.

    PubMed

    He, Songbing; Fei, Min; Wu, Yugang; Zheng, Dingcheng; Wan, Daiwei; Wang, Liang; Li, Dechun

    2011-01-01

    This study was designed to investigate the distribution of Th17 cells in the tumor microenvironment and peripheral blood of pancreatic cancer patients, its clinical significance, and the expression profile of Th17 cell-associated cytokines. The percentage of Th17 cells detected by flow cytometry analysis (FACS) was significantly higher in 46 pancreatic tumor tissues (5.28 ± 1.65%) compared with corresponding adjacent normal tissues (2.57 ± 0.83%) (P = 0.031). In addition, the percentage of Th17 cells was significantly higher in stage III-IV tumors than stage I-II tumors (P = 0.039). The percentage of Th17 cells in peripheral blood of 20 pancreatic cancer patients (3.99 ± 1.15%) was significantly higher than 15 healthy volunteers (1.98 ± 0.57%) (P = 0.027). Immunohistochemistry (IHC) was performed to detect IL-17(+) cells in 46 pancreatic tumor tissues, as well as expression of CD34 in 24 tumor tissues. IL-17 was shown to mainly locate in cytoplasm, and the frequency of IL-17(+) cells in tumor tissues (39/46) was higher than control (29/46). The presence of IL-17(+) cells in tumor tissues was associated with tumor, node, and metastasis (TNM) stage, and lymph node metastasis (P = 0.012 and P = 0.009) but not with patient sex, age, tumor size, and histological grade (P > 0.05). Interestingly, distribution of Th17 cells in tumor tissues was positively correlated with microvessel density (MVD) (r = 0.86, P = 0.018). Furthermore, the median survival time of patients with high and low level of IL-17(+) cells frequency was 14.5 and 18.5 months respectively (P = 0.023). The serum levels of Th17 cell-associated cytokines, IL-17 and IL-23 in 20 pancreatic patients detected by enzyme-linked immunosorbent assay (ELISA) were 69.2 ± 28.5 pg/mL and 266.5 ± 98.1 pg/mL, respectively, which were significantly higher than 15 healthy volunteers (P = 0.015 and P = 0.02). Moreover, levels of IL-17 and IL-23 were significantly higher in stage III-IV tumors than stage I-II tumors (P

  19. Effect of Audio Coaching on Correlation of Abdominal Displacement With Lung Tumor Motion

    SciTech Connect

    Nakamura, Mitsuhiro Narita, Yuichiro; Matsuo, Yukinori; Narabayashi, Masaru; Nakata, Manabu; Sawada, Akira; Mizowaki, Takashi; Nagata, Yasushi; Hiraoka, Masahiro

    2009-10-01

    Purpose: To assess the effect of audio coaching on the time-dependent behavior of the correlation between abdominal motion and lung tumor motion and the corresponding lung tumor position mismatches. Methods and Materials: Six patients who had a lung tumor with a motion range >8 mm were enrolled in the present study. Breathing-synchronized fluoroscopy was performed initially without audio coaching, followed by fluoroscopy with recorded audio coaching for multiple days. Two different measurements, anteroposterior abdominal displacement using the real-time positioning management system and superoinferior (SI) lung tumor motion by X-ray fluoroscopy, were performed simultaneously. Their sequential images were recorded using one display system. The lung tumor position was automatically detected with a template matching technique. The relationship between the abdominal and lung tumor motion was analyzed with and without audio coaching. Results: The mean SI tumor displacement was 10.4 mm without audio coaching and increased to 23.0 mm with audio coaching (p < .01). The correlation coefficients ranged from 0.89 to 0.97 with free breathing. Applying audio coaching, the correlation coefficients improved significantly (range, 0.93-0.99; p < .01), and the SI lung tumor position mismatches became larger in 75% of all sessions. Conclusion: Audio coaching served to increase the degree of correlation and make it more reproducible. In addition, the phase shifts between tumor motion and abdominal displacement were improved; however, all patients breathed more deeply, and the SI lung tumor position mismatches became slightly larger with audio coaching than without audio coaching.

  20. A PAUF-neutralizing antibody targets both carcinoma and endothelial cells to impede pancreatic tumor progression and metastasis

    SciTech Connect

    Kim, Su Jin; Chang, Suhwan; Lee, Yangsoon; Kim, Na Young; Hwang, Yeonsil; Min, Hye Jin; Yoo, Kyung-Sook; Park, Eun Hye; Kim, Seokho; Chung, Young-Hwa; Park, Young Woo; Koh, Sang Seok

    2014-11-07

    Highlights: • PMAb83, a human monoclonal antibody against PAUF, impaired tumor progression in vivo. • PMAb83 attenuated aggressiveness of tumor cells and suppressed angiogenesis. • PMAb83 in combination with gemcitabine conferred improved survival of mouse model. - Abstract: Pancreatic adenocarcinoma up-regulated factor (PAUF) is expressed in pancreatic ductal adenocarcinoma (PDAC) and plays an important role in tumor progression and metastasis. Here we evaluate the anti-tumor efficacy of a human monoclonal antibody against PAUF, PMAb83, to provide a therapeutic intervention to treat the disease. PMAb83 reduced tumor growth and distant metastasis in orthotopically xenografted mice of human PDAC cells. PMAb83 treatment retarded proliferation along with weakened aggressiveness traits of the carcinoma cells. AKT/β-catenin signaling played a role in the carcinoma cell proliferation and the treated xenograft tumors exhibited reduced levels of β-catenin and cyclin D1. Moreover PMAb83 abrogated the PAUF-induced angiogenic responses of endothelial cells, reducing the density of CD31{sup +} vessels in the treated tumors. In combination with gemcitabine, PMAb83 conferred enhanced survival of xenografted mice by about twofold compared to gemcitabine alone. Taken together, our findings show that PMAb83 treatment decreases the aggressiveness of carcinoma cells and suppresses tumor vascularization, which culminates in mitigated tumor growth and metastasis with improved survival in PDAC mouse models.

  1. Non-specific internalization of laser ablated pure gold nanoparticles in pancreatic tumor cell.

    PubMed

    Sobhan, M A; Sreenivasan, V K A; Withford, M J; Goldys, E M

    2012-04-01

    We investigate the intracellular uptake of 7.3 nm, 21.2 nm and 31.3 nm average size pure colloidal gold nanoparticles synthesized using femtosecond laser ablation technique in pure water. Dark-field imaging, transmission electron microscopy (TEM) and scanning electron microscopy (SEM) was used to assess the uptake of these pure gold nanoparticles in the pancreatic tumor cell line. We show that these ligand-free gold nanoparticles are non-toxic to these cells. The nanoparticles and cell images indicated that unmodified gold nanoparticles interacted with the cells, despite negative surface charge on both the cells and the nanoparticles. We also demonstrate that the uptake of the gold nanoparticles is size-dependent.

  2. Chronic cadmium exposure in vitro causes acquisition of multiple tumor cell characteristics in human pancreatic epithelial cells.

    PubMed

    Qu, Wei; Tokar, Erik J; Kim, Andrew J; Bell, Matthew W; Waalkes, Michael P

    2012-09-01

    Cancer may be a stem cell (SC)-based disease involving formation of cancer SCs (CSCs) potentially arising from transformation of normal SCs. Cadmium has been linked to human pancreatic cancer. We studied cadmium exposure of human pancreatic ductal epithelial (HPDE) cells and whether SCs may be targeted in this process. We chronically exposed HPDE cells to low level cadmium (1 μM) for ≤ 29 weeks. Nonadherent spheroid formation was used to indicate CSC-like cell production, and we assessed tumor cell characteristics in such spheres. Assessed tumor cell characteristics including secretion of matrix metalloproteinase-9 (MMP-9), invasion, and colony formation were fortified by evaluating expression of relevant genes by real-time reverse transcription polymerase chain reaction and by Western blot. Increased MMP-9 secretion and overexpression of the pancreatic cancer marker S100P occurred in chronic (29 weeks of exposure) cadmium-exposed (CCE) cells. CCE cells also showed markedly higher colony formation and invasion, typical of cancer cells. Floating "spheres" of viable cells, known to contain an abundance of normal SCs or CSCs, form in vitro with many cell types. CCE cells produced 3-fold more spheres than control cells and were more invasive, secreted more MMP-9, and overexpressed markers for pancreatic SCs/CSCs (i.e., CXCR4, OCT4, CD44) and S100P, a marker for pancreatic cancer. CCE-derived spheres rapidly produced aggressive, highly branched, and poorly differentiated glandular-like structures in Matrigel. Chronic cadmium exposure produced multiple tumor cell characteristics in HPDE cells and CCE cell-derived spheres. These data support the plausibility of cadmium as a human pancreatic carcinogen.

  3. Prediction of survival and tumor recurrence in patients undergoing surgery for pancreatic neuroendocrine neoplasms.

    PubMed

    Kaltenborn, Alexander; Matzke, Svenja; Kleine, Moritz; Krech, Till; Ramackers, Wolf; Vondran, Florian W R; Klempnauer, Jürgen; Bektas, Hüseyin; Schrem, Harald

    2016-02-01

    This study strives to define prognostic models for outcome after surgery for malignant pancreatic neuroendocrine tumors. Forty-one patients were included. Prognostic models for mortality and disease recurrence were developed with multivariate binary logistic regression. The proposed prognostic model for tumor recurrence risk after surgery in percentage (AUROC = 0.774, 95%CI = 0.611-0.937) is: Risk in % = Exp(Y)/(1 + Exp(Y)), with Y = -4.360 + (0.015 × tumor diameter in cm) + (0.010 × preoperative platelet count in thousand/μl) + (1.077 × distant metastases, if yes = 1; if no = 0) + (-0.026 × Ki-67-positive cells in %) + (-1.086 × upper abdominal pain, if yes = 1; if no = 0). The proposed prognostic model for observed 3-year survival probability after surgery in % (AUROC = 0.932, 95%CI = 0.857-0.999) is: Survival probability in % = Exp(Y)/(1 + Exp(Y)), with Y = -12.492 + (0.054 × preoperative platelet count in thousand/μl) + (0.112 × minimal distance of the resection margin from the tumor in mm) + (-1.574 × number of positive lymph nodes) + (2.292 × histological tumor infiltration, if yes = 1; if no = 0) CONCLUSIONS: The platelet count was identified as a relevant risk factor. Proposed prognostic models with good model-fit display properties that indicate potential clinical usefulness. © 2015 Wiley Periodicals, Inc.

  4. CBP-mediated FOXO-1 acetylation inhibits pancreatic tumor growth by targeting SirT.

    PubMed

    Pramanik, Kartick C; Fofaria, Neel M; Gupta, Parul; Srivastava, Sanjay K

    2014-03-01

    Here, we investigated the potential mechanism of capsaicin-mediated apoptosis in pancreatic cancer cells. Capsaicin treatment phosphorylated c-jun-NH2-kinase (JNK); forkhead box transcription factor, class O (FOXO1); and BIM in BxPC-3, AsPC-1, and L3.6PL cells. The expression of BIM increased in response to capsaicin treatment. Capsaicin treatment caused cleavage of caspase-3 and PARP, indicating apoptosis. Antioxidants tiron and PEG-catalase blocked capsaicin-mediated JNK/FOXO/BIM activation and protected the cells from apoptosis. Furthermore, capsaicin treatment caused a steady increase in the nuclear expression of FOXO-1, leading to increased DNA binding. Capsaicin-mediated expression of BIM was found to be directly dependent on the acetylation of FOXO-1. The expression of CREB-binding protein (CBP) was increased, whereas SirT-1 was reduced by capsaicin treatment. Using acetylation mimic or defective mutants, our result demonstrated that phosphorylation of FOXO-1 was mediated through acetylation by capsaicin treatment. JNK inhibitor attenuated the phosphorylation of FOXO-1, activation of BIM, and abrogated capsaicin-induced apoptosis. Moreover, silencing FOXO1 by siRNA blocked capsaicin-mediated activation of BIM and apoptosis, whereas overexpression of FOXO-1 augmented its effects. Silencing Bim drastically reduced capsaicin-mediated cleavage of caspase-3 and PARP, indicating the role of BIM in apoptosis. Oral administration of 5 mg/kg capsaicin substantially suppressed the growth of BxPC-3 tumor xenografts in athymic nude mice. Tumors from capsaicin-treated mice showed an increase in the phosphorylation of JNK, FOXO-1, BIM, and levels of CBP, cleavage of caspase-3, PARP, and decreased SirT-1 expression. Taken together, our results suggest that capsaicin activated JNK and FOXO-1, leading to the acetylation of FOXO-1 through CBP and SirT-1. Acetylated FOXO1 induced apoptosis in pancreatic cancer cells through BIM activation.

  5. Association between ABO blood types and sporadic pancreatic neuroendocrine tumors in the Chinese Han population.

    PubMed

    Ben, Qiwen; Liu, Jun; Wang, Weiyi; Guo, Fang; Yao, Weiyan; Zhong, Jie; Yuan, Yaozong

    2017-08-15

    Although the relationship between non-O blood types and the risk of exocrine pancreatic cancer has been demonstrated, the association between ABO blood types and sporadic pancreatic neuroendocrine tumor (PNET) has not been reported thus far. This hospital-based, case-control study included 387 patients with PNET and 542 age- and sex-matched controls. Unconditional multivariable logistic regression analysis was performed to estimate the adjusted odds ratios (AORs) and 95% confidence intervals (CIs). The relationship between ABO blood types and clinicopathologic features was also analyzed. After adjusting for age, sex, smoking status, alcohol drinking, and first-degree family history of any cancer, the AORs (95% CI) of functional PNET were 0.87 (0.59-1.28) for blood type A, 0.86 (0.58-1.28) for blood type B, and 0.71 (0.39-1.26) for blood type AB compared with subjects with blood type O. A similar ABO blood-type distribution was observed among cases with non-functional PNETs compared with controls. On comparing blood type B with non-B blood type, cases with non-functional PNETs had marginally higher rates of lymph node invasion (P = 0.047), distant metastasis (P = 0.044), and advanced European Neuroendocrine Tumor Society Stage (P = 0.040). There is no association between the ABO blood group and the development of functional and non-functional PNETs. The ABO blood types are not associated with the clinicopathologic features in patients with functional and non-functional PNETs.

  6. The Phosphatase PHLPP1 Regulates Akt2, Promotes Pancreatic Cancer Cell Death, and Inhibits Tumor Formation

    PubMed Central

    NITSCHE, CLAUDIA; EDDERKAOUI, MOUAD; MOORE, RYAN M.; EIBL, GUIDO; KASAHARA, NORIYUKI; TREGER, JANET; GRIPPO, PAUL J.; MAYERLE, JULIA; LERCH, MARKUS M.; GUKOVSKAYA, ANNA S.

    2015-01-01

    BACKGROUND & AIMS The kinase Akt mediates resistance of pancreatic cancer (PaCa) cells to death and is constitutively active (phosphorylated) in cancer cells. Whereas the kinases that activate Akt are well characterized, less is known about phosphatases that dephosporylate and thereby inactivate it. We investigated regulation of Akt activity and cell death by the phosphatases PHLPP1 and PHLPP2 in PaCa cells, mouse models of PaCa, and human pancreatic ductal adenocarcinoma (PDAC). METHODS We measured the effects of PHLPP overexpression or knockdown with small interfering RNAs on Akt activation and cell death. We examined regulation of PHLPPs by growth factors and reactive oxygen species, as well as associations between PHLPPs and tumorigenesis. RESULTS PHLPP overexpression inactivated Akt, whereas PHLPP knockdown increased phosphorylation of Akt in PaCa cells. Levels of PHLPPs were greatly reduced in human PDAC and in mouse genetic and xenograft models of PaCa. PHLPP activities in PaCa cells were down-regulated by growth factors and Nox4 reduced nicotinamide adenine dinucleotide phosphate oxidase. PHLPP1 selectively dephosphorylated Akt2, whereas PHLPP2 selectively dephosphorylated Akt1. Akt2, but not Akt1, was up-regulated in PDAC, and Akt2 levels correlated with mortality. Consistent with these results, high levels of PHLPP1, which dephosphorylates Akt2 (but not PHLPP2, which dephosphorylates Akt1), correlated with longer survival times of patients with PDAC. In mice, xenograft tumors derived from PaCa cells that overexpress PHLPP1 (but not PHLPP2) had inactivated Akt, greater extent of apoptosis, and smaller size. CONCLUSIONS PHLPP1 has tumor suppressive activity and might represent a therapeutic or diagnostic tool for PDAC. PMID:22044669

  7. GLP1 and glucagon co-secreting pancreatic neuroendocrine tumor presenting as hypoglycemia after gastric bypass

    PubMed Central

    Guimarães, Marta; Rodrigues, Pedro; Pereira, Sofia S; Nora, Mário; Gonçalves, Gil; Albrechtsen, Nicolai Wewer; Hartmann, Bolette; Holst, Jens Juul

    2015-01-01

    Summary Post-prandial hypoglycemia is frequently found after bariatric surgery. Although rare, pancreatic neuroendocrine tumors (pNET), which occasionally are mixed hormone secreting, can lead to atypical clinical manifestations, including reactive hypoglycemia. Two years after gastric bypass surgery for the treatment of severe obesity, a 54-year-old female with previous type 2 diabetes, developed post-prandial sweating, fainting and hypoglycemic episodes, which eventually led to the finding by ultrasound of a 1.8-cm solid mass in the pancreatic head. The 72-h fast test and the plasma chromogranin A levels were normal but octreotide scintigraphy showed a single focus of abnormal radiotracer uptake at the site of the nodule. There were no other clinical signs of hormone secreting pNET and gastrointestinal hormone measurements were not performed. The patient underwent surgical enucleation with complete remission of the hypoglycemic episodes. Histopathology revealed a well-differentiated neuroendocrine carcinoma with low-grade malignancy with positive chromogranin A and glucagon immunostaining. An extract of the resected tumor contained a high concentration of glucagon (26.707 pmol/g tissue), in addition to traces of GLP1 (471 pmol/g), insulin (139 pmol/g) and somatostatin (23 pmol/g). This is the first report of a GLP1 and glucagon co-secreting pNET presenting as hypoglycemia after gastric bypass surgery. Although pNET are rare, they should be considered in the differential diagnosis of the clinical approach to the post-bariatric surgery hypoglycemia patient. Learning points pNETs can be multihormonal-secreting, leading to atypical clinical manifestations.Reactive hypoglycemic episodes are frequent after gastric bypass.pNETs should be considered in the differential diagnosis of hypoglycemia after bariatric surgery. PMID:26266036

  8. STAT3 Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer

    PubMed Central

    Nagathihalli, Nagaraj S.; Castellanos, Jason A.; Shi, Chanjuan; Beesetty, Yugandhar; Reyzer, Michelle L.; Caprioli, Richard; Chen, Xi; Walsh, Alex J.; Skala, Melissa C.; Moses, Harold L.; Merchant, Nipun B.

    2015-01-01

    BACKGROUND & AIMS A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified STAT3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance. METHODS Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by MALDI-imaging mass spectrometry. Collagen second harmonic generation (SHG) imaging quantified tumor collagen alignment and density. RESULTS STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma and downregulation of cytidine deaminase (Cda). CONCLUSIONS Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and downregulation of Cda without depletion of tumor stromal content. PMID:26255562

  9. A rare case of metastasized non-functional pancreatic neuroendocrine tumor with a good long-term survival

    PubMed Central

    Mirică, A; Bădărău, IA; Mirică, R; Păun, S; Păun, DL

    2016-01-01

    Background: Non-functional neuroendocrine tumors of the pancreas (NF-pNETs) are a varied group of extremely rare malignancies. The majority of patients already have liver metastases at the diagnosis moment, thus, treatment options are restricted, and the survival rate is reserved. Case report: We presented the case of 59-year-old patient, diagnosed with non-functional well-differentiated pancreatic neuroendocrine tumor grade II (NET G2) with the presence of chromogranin A, synaptophysin and somatostatin receptor 2, together with liver and bone metastases. Patient underwent a surgical excision of the pancreatic tumor, started long-acting somatostatin analogues (octreotide), interferon therapy for liver metastases and local radiotherapy for bone metastases. After one year, the patient developed diabetes, needing insulin therapy. At approximately three years after the diagnosis, the patient was still living, had a good quality of life, and was free of local recurrence of the tumor or other metastases. Conclusion: Our case report presented a rare case of metastatic non-functional well-differentiated pancreatic neuroendocrine tumor, involving a multidisciplinary therapeutic approach in order to obtain a good long-term survival. PMID:27928440

  10. A rare case of metastasized non-functional pancreatic neuroendocrine tumor with a good long-term survival.

    PubMed

    A, Mirică; Ia, Bădărău; R, Mirică; S, Păun; Dl, Păun

    2016-01-01

    Background: Non-functional neuroendocrine tumors of the pancreas (NF-pNETs) are a varied group of extremely rare malignancies. The majority of patients already have liver metastases at the diagnosis moment, thus, treatment options are restricted, and the survival rate is reserved. Case report: We presented the case of 59-year-old patient, diagnosed with non-functional well-differentiated pancreatic neuroendocrine tumor grade II (NET G2) with the presence of chromogranin A, synaptophysin and somatostatin receptor 2, together with liver and bone metastases. Patient underwent a surgical excision of the pancreatic tumor, started long-acting somatostatin analogues (octreotide), interferon therapy for liver metastases and local radiotherapy for bone metastases. After one year, the patient developed diabetes, needing insulin therapy. At approximately three years after the diagnosis, the patient was still living, had a good quality of life, and was free of local recurrence of the tumor or other metastases. Conclusion: Our case report presented a rare case of metastatic non-functional well-differentiated pancreatic neuroendocrine tumor, involving a multidisciplinary therapeutic approach in order to obtain a good long-term survival.

  11. The somatostatin analog 188Re-P2045 inhibits the growth of AR42J pancreatic tumor xenografts.

    PubMed

    Nelson, Carol A; Azure, Michael T; Adams, Christopher T; Zinn, Kurt R

    2014-12-01

    P2045 is a peptide analog of somatostatin with picomolar affinity for the somatostatin receptor subtype 2 (SSTR2) upregulated in some pancreatic tumors. Studies were conducted in rat AR42J pancreatic tumor xenograft mice to determine whether (188)Re-P2045 could inhibit the growth of pancreatic cancer in an animal model. (188)Re-P2045 was intravenously administered every 3 d for 16 d to nude mice with AR42J tumor xenografts that were approximately 20 mm(3) at study initiation. Tumor volumes were recorded throughout the dosing period. At necropsy, all tissues were assessed for levels of radioactivity and evaluated for histologic abnormalities. Clinical chemistry and hematology parameters were determined from terminal blood samples. The affinity of nonradioactive (185/187)Re-P2045 for somatostatin receptors was compared in human NCI-H69 and rat AR42J tumor cell membranes expressing predominantly SSTR2. In the 1.85- and 5.55-MBq groups, tumor growth was inhibited in a dose-dependent fashion. In the 11.1-MBq group, tumor growth was completely inhibited throughout the dosing period and for 12 d after the last administered dose. The radioactivity level in tumors 4 h after injection was 10 percentage injected dose per gram, which was 2-fold higher than in the kidneys. (188)Re-P2045 was well tolerated in all dose groups, with no adverse clinical, histologic, or hematologic findings. The nonradioactive (185/187)Re-P2045 bound more avidly (0.2 nM) to SSTR2 in human than rat tumor membranes, suggesting that these studies are relevant to human studies. (188)Re-P2045 is a promising therapeutic candidate for patients with somatostatin receptor-positive cancer. © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  12. Genetic polymorphisms of inflammatory response gene TNF-α and its influence on sporadic pancreatic neuroendocrine tumors predisposition risk.

    PubMed

    Karakaxas, Dimitrios; Gazouli, Maria; Coker, Ahmet; Agalianos, Christos; Papanikolaou, Ioannis S; Patapis, Pavlos; Liakakos, Theodoros; Dervenis, Christos

    2014-10-01

    The diagnosed incidence of pancreatic neuroendocrine tumors (pNETs) is increasing; however, their etiology remains poorly understood. PNETs are a rare, heterogeneous group of tumors arising from the endocrine cells of the pancreas, and genetic risk factors for sporadic pNETs are inadequately understood. It is known that pNETs secrete biogenic amines, hormones and growth factors, tumor necrosis factor-a (TNF-α) being one of them. Furthermore, cytokines and other proinflammatory mediators have been implicated in inflammatory pancreatic diseases including pancreatitis and cancer. The aim of our study was to analyze TNF-α promoter gene polymorphisms as risk factors for pNETs using germline DNA collected in a population-based case-control study of pancreatic cancer [42 pNET cases, 78 pancreatic ductal adenocarcinoma (PDAC) cases, 17 intraductal papillary mucinous neoplasm (IPMN) and 98 healthy controls] conducted in the Athens, Greece and Izmir, Turkey areas. For subsequent analysis, we excluded cases and controls with known genetic syndromes. The CC genotype at the -1031 position was more frequent in pNET and IPMN patients (p=0.0002 and p=0.009, respectively), suggesting its possible role in pNET development. Furthermore, the AA genotype at the -308 position was overrepresented in IPMN cases (p=0.03), and AA genotype at the -238 position was more frequent in PDAC cases (p=0.03) compared to healthy individuals. With regard to tumor characteristics, no statistically significant association was detected. Our findings suggest the putative role of TNF-α -1031 polymorphism in the development of pNET and IPMN, whereas the -308 polymorphism seems to be overrepresented among IPMN cases and -238 polymorphism among PDAC cases.

  13. Fear of cancer recurrence after curative pancreatectomy: a cross-sectional study in survivors of pancreatic and periampullary tumors.

    PubMed

    Petzel, Maria Q B; Parker, Nathan H; Valentine, Alan D; Simard, Sébastien; Nogueras-Gonzalez, Graciela M; Lee, Jeffrey E; Pisters, Peter W T; Vauthey, Jean-Nicolas; Fleming, Jason B; Katz, Matthew H G

    2012-12-01

    Fear of disease recurrence is well documented among cancer survivors, but its significance among patients treated for solid pancreatic and periampullary neoplasms is unknown despite the known risk of recurrence associated with these tumors. We hypothesized that fear of cancer recurrence (FCR) represents a common source of psychosocial distress in this population and sought to characterize subgroups for whom FCR might represent a target for intervention to improve quality of life. We conducted a cross-sectional study of FCR in patients who were disease-free after potentially curative pancreatectomy for ductal or periampullary adenocarcinoma or pancreatic neuroendocrine tumor. We assessed seven discrete dimensions of FCR using the Fear of Recurrence Inventory and evaluated quality of life and psychosocial distress using the Functional Assessment of Cancer Therapy-Hepatobiliary Questionnaire and the Hospital Anxiety and Depression Scale. Of 354 eligible patients, 240 (68 %) participated in the study a median of 48 months after potentially curative pancreatectomy. An FCR severity score indicative of frequent fearful thoughts, emotional disturbance and functional impairment was identified in 37, 28, and 35 % of patients with pancreatic adenocarcinoma, nonpancreatic periampullary adenocarcinoma, and pancreatic neuroendocrine tumor, respectively. Anxiety (P < 0.001) and low quality of life (P = 0.028) were independently associated with a clinically significant level of FCR, but histopathologic diagnosis and clinicopathologic markers of prognosis were not. FCR represents a significant concern for one-third of patients after curative surgery for a pancreatic or periampullary tumor, regardless of their actual likelihood of recurrence or disease-related death.

  14. Development of an endoluminal high-intensity ultrasound applicator for image-guided thermal therapy of pancreatic tumors

    PubMed Central

    Scott, Serena J.; Salgaonkar, Vasant A.; Jones, Peter D.; Plata-Camargo, Juan C.; Sommer, Graham; Diederich, Chris J.

    2015-01-01

    An ultrasound applicator for endoluminal thermal therapy of pancreatic tumors has been introduced and evaluated through acoustic/biothermal simulations and ex vivo experimental investigations. Endoluminal therapeutic ultrasound constitutes a minimally invinvasive conformal therapy and is compatible with ultrasound or MR-based image guidance. The applicator would be placed in the stomach or duodenal lumen, and sonication would be performed through the luminal wall into the tumor, with concurrent water cooling of the wall tissue to prevent its thermal injury. A finite-element (FEM) 3D acoustic and biothermal model was implemented for theoretical analysis of the approach. Parametric studies over transducer geometries and frequencies revealed that operating frequencies within 1-3 MHz maximize penetration depth and lesion volume while sparing damage to the luminal wall. Patient-specific FEM models of pancreatic head tumors were generated and used to assess the feasibility of performing endoluminal ultrasound thermal ablation and hyperthermia of pancreatic tumors. Results indicated over 80% of the volume of small tumors (~2 cm diameter) within 35 mm of the duodenum could be safely ablated in under 30 minutes or elevated to hyperthermic temperatures at steady-state. Approximately 60% of a large tumor (~5 cm diameter) model could be safely ablated by considering multiple positions of the applicator along the length of the duodenum to increase coverage. Prototype applicators containing two 3.2 MHz planar transducers were fabricated and evaluated in ex vivo porcine carcass heating experiments under MR temperature imaging (MRTI) guidance. The applicator was positioned in the stomach adjacent to the pancreas, and sonications were performed for 10 min at 5 W/cm2 applied intensity. MRTI indicated over 40°C temperature rise in pancreatic tissue with heating penetration extending 3 cm from the luminal wall. PMID:26677314

  15. Development of an endoluminal high-intensity ultrasound applicator for image-guided thermal therapy of pancreatic tumors

    NASA Astrophysics Data System (ADS)

    Adams, Matthew S.; Scott, Serena J.; Salgaonkar, Vasant A.; Jones, Peter D.; Plata-Camargo, Juan C.; Sommer, Graham; Diederich, Chris J.

    2015-03-01

    An ultrasound applicator for endoluminal thermal therapy of pancreatic tumors has been introduced and evaluated through acoustic/biothermal simulations and ex vivo experimental investigations. Endoluminal therapeutic ultrasound constitutes a minimally invasive conformal therapy and is compatible with ultrasound or MR-based image guidance. The applicator would be placed in the stomach or duodenal lumen, and sonication would be performed through the luminal wall into the tumor, with concurrent water cooling of the wall tissue to prevent its thermal injury. A finite-element (FEM) 3D acoustic and biothermal model was implemented for theoretical analysis of the approach. Parametric studies over transducer geometries and frequencies revealed that operating frequencies within 1-3 MHz maximize penetration depth and lesion volume while sparing damage to the luminal wall. Patient-specific FEM models of pancreatic head tumors were generated and used to assess the feasibility of performing endoluminal ultrasound thermal ablation and hyperthermia of pancreatic tumors. Results indicated over 80% of the volume of small tumors (~2 cm diameter) within 35 mm of the duodenum could be safely ablated in under 30 minutes or elevated to hyperthermic temperatures at steady-state. Approximately 60% of a large tumor (~5 cm diameter) model could be safely ablated by considering multiple positions of the applicator along the length of the duodenum to increase coverage. Prototype applicators containing two 3.2 MHz planar transducers were fabricated and evaluated in ex vivo porcine carcass heating experiments under MR temperature imaging (MRTI) guidance. The applicator was positioned in the stomach adjacent to the pancreas, and sonications were performed for 10 min at 5 W/cm2 applied intensity. MRTI indicated over 400C temperature rise in pancreatic tissue with heating penetration extending 3 cm from the luminal wall.

  16. Leveraging respiratory organ motion for non-invasive tumor treatment devices: a feasibility study

    NASA Astrophysics Data System (ADS)

    Möri, Nadia; Jud, Christoph; Salomir, Rares; Cattin, Philippe C.

    2016-06-01

    In noninvasive abdominal tumor treatment, research has focused on minimizing organ motion either by gating, breath holding or tracking of the target. The paradigm shift proposed in this study takes advantage of the respiratory organ motion to passively scan the tumor. In the proposed self-scanning method, the focal point of the HIFU device is held fixed for a given time, while it passively scans the tumor due to breathing motion. The aim of this paper is to present a treatment planning method for such a system and show by simulation its feasibility. The presented planning method minimizes treatment time and ensures complete tumor ablation under free-breathing. We simulated our method on realistic motion patterns from a patient specific statistical respiratory model. With our method, we achieved a shorter treatment time than with the gold-standard motion-compensation approach. The main advantage of the proposed method is that electrically steering of the focal spot is no longer needed. As a consequence, it is much easier to find an optimal solution for both avoiding near field heating and covering the whole tumor. However, the reduced complexity on the beam forming comes at the price of an increased complexity on the planning side as well as a reduced efficiency in the energy distribution. Although we simulate the approach on HIFU, the idea of self-scanning passes over to other tumor treatment modalities such as proton therapy or classical radiation therapy.

  17. Dosimetric effect of intrafraction tumor motion in phase gated lung stereotactic body radiotherapy

    SciTech Connect

    Zhao Bo; Yang Yong; Li Tianfang; Li Xiang; Heron, Dwight E.; Huq, M. Saiful

    2012-11-15

    Purpose: A major concern for lung intensity modulated radiation therapy delivery is the deviation of actually delivered dose distribution from the planned one due to simultaneous movements of multileaf collimator (MLC) leaves and tumor. For gated lung stereotactic body radiotherapy treatment (SBRT), the situation becomes even more complicated because of SBRT's characteristics such as fewer fractions, smaller target volume, higher dose rate, and extended fractional treatment time. The purpose of this work is to investigate the dosimetric effect of intrafraction tumor motion during gated lung SBRT delivery by reconstructing the delivered dose distribution with real-time tumor motion considered. Methods: The tumor motion data were retrieved from six lung patients. Each of them received three fractions of stereotactic radiotherapy treatments with Cyberknife Synchrony (Accuray, Sunnyvale, CA). Phase gating through an external surrogate was simulated with a gating window of 5 mm. The resulting residual tumor motion curves during gating (beam-on) were retrieved. Planning target volume (PTV) was defined as physician-contoured clinical target volume (CTV) surrounded by an isotropic 5 mm margin. Each patient was prescribed with 60 Gy/3 fractions. The authors developed an algorithm to reconstruct the delivered dose with tumor motion. The DMLC segments, mainly leaf position and segment weighting factor, were recalculated according to the probability density function of tumor motion curve. The new DMLC sequence file was imported back to treatment planning system to reconstruct the dose distribution. Results: Half of the patients in the study group experienced PTV D95% deviation up to 26% for fractional dose and 14% for total dose. CTV mean dose dropped by 1% with tumor motion. Although CTV is almost covered by prescribed dose with 5 mm margin, qualitative comparison on the dose distributions reveals that CTV is on the verge of underdose. The discrepancy happens due to tumor

  18. A Tumorigenic Factor Interactome Connected Through Tumor Suppressor MicroRNA-198 in Human Pancreatic Cancer

    PubMed Central

    Marin-Muller, Christian; Li, Dali; Bharadwaj, Uddalak; Li, Min; Chen, Changyi; Hodges, Sally E.; Fisher, William E.; Mo, Qianxing; Hung, Mien-Chie; Yao, Qizhi

    2013-01-01

    Purpose The majority of pancreatic cancers (PCs) overexpress mesothelin (MSLN), which contributes to enhanced proliferation, invasion and migration. However, the MSLN regulatory network is still unclear. Here, we investigated the regulation of a panel of tumorigenic factors, and explored the potential of MSLN regulated miR-198 treatment in vivo. Experimental Design The expression and functional regulation of the tumorigenic factors MSLN, NF-κB, and the homeobox transcription factors (TFs) POU2F2 (OCT-2), Pre-B-cell leukemia homeobox factor 1 (PBX-1), valosin-containing protein (VCP), and miR-198 were studied in PC cell lines, patient tumor samples and in xenograft PC mouse models. Results We found that miR-198 is downregulated in PC and is involved in an intricate reciprocal regulatory loop with MSLN, which represses miR-198 through NF-κB-mediated OCT-2 induction. Furthermore, miR-198 repression leads to overexpression of PBX-1 and VCP. The dysregulated PBX-1/VCP axis leads to increased tumorigenicity. Reconstitution of miR-198 in PC cells results in reduced tumor growth, metastasis, and increased survival through direct targeting MSLN, PBX-1, and VCP. Most interestingly, reduced levels of miR-198 in human tissue samples are associated with upregulation of these tumorigenic factors (MSLN, OCT-2, PBX-1, VCP) and predict poor survival. Reduced miR-198 expression links this tumor network signature and prognosticates poor patient outcome. High miR-198 disrupts the network and predicts better prognosis and increased survival. Conclusions MiR-198 acts as a central tumor suppressor and modulates the molecular makeup of a critical interactome in PC, indicating a potential prognostic marker signature and the therapeutic potential of attacking this tumorigenic network through a central vantage point. PMID:23989979

  19. Everolimus in the treatment of patients with advanced pancreatic neuroendocrine tumors: latest findings and interpretations

    PubMed Central

    Liu, Eric; Marincola, Paula

    2013-01-01

    Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms with various clinical presentations. More than half of patients present with so-called nonfunctioning tumors with no hormone-related symptoms, whereas other tumors produce symptoms like gastric problems, ulcers, hypoglycemia, skin rash and diarrhea related to hormone production. The traditional treatment for pNETs over the last three decades has been cytotoxic agents, mainly streptozotocin plus 5-fluorouracil or doxorubicin. Most recently two new compounds have been registered worldwide for the treatment of pNETs, the mammalian target of rapamycin (mTOR) inhibitor everolimus and the tyrosine kinase inhibitor sunitinib. This paper concentrates on the use of mTOR inhibitors and the mechanisms of action. The mTOR pathway is altered in a number of pNETs. Everolimus (RAD001) is an orally active rapamycin analog and mTOR inhibitor. It blocks activity of the mTOR pathway by binding with high affinity to the cytoplasmic protein FKBP-12. The efficacy of everolimus in pNETs has been demonstrated in two multicenter studies (RADIANT 1 and 3). The RADIANT 3 study was a randomized controlled study in pNETs of everolimus 10 mg/day versus placebo, showing an increased progression-free survival (11.7 months versus 4.6 months) and hazard ratio of 0.35 (p < 0.001). Current studies indicate that there is strong evidence to support the antitumor effect of rapalogs in pNETs. However, significant tumor reduction is very rarely obtained, usually in less than 10% of treated patients. Therefore, these drugs may be more effective in combination with other anticancer agents, including chemotherapy, targeted therapies as well as peptide receptor radiotherapy. PMID:24003341

  20. Tumor motion changes in stereotactic body radiotherapy for liver tumors: an evaluation based on four-dimensional cone-beam computed tomography and fiducial markers.

    PubMed

    Shimohigashi, Yoshinobu; Toya, Ryo; Saito, Tetsuo; Ikeda, Osamu; Maruyama, Masato; Yonemura, Keisuke; Nakaguchi, Yuji; Kai, Yudai; Yamashita, Yasuyuki; Oya, Natsuo; Araki, Fujio

    2017-03-23

    For stereotactic body radiation therapy (SBRT) of liver tumors, tumor motion induced by respiration must be taken into account in planning and treatment. We evaluated whether liver tumor motion at the planning simulation represents liver tumor motion during SBRT, and estimated inter- and intrafractional tumor motion changes in patients undergoing liver SBRT. Ten patients underwent four-dimensional cone-beam computed tomography (4D-CBCT) image-guided liver SBRT with abdominal compression (AC) and fiducial markers. 4D-CBCT was performed to evaluate liver tumor motion at the planning simulation, pre-, and post-SBRT. The translational distances at the center position of the fiducial markers from all 10 phases on the 4D-CBCT images were measured as the extent of the liver tumor motion in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions. Pearson correlation coefficients were calculated to evaluate the correlation between liver tumor motion of the planning simulation and the mean liver tumor motion of the pre-SBRT. Inter- and intrafractional liver tumor motion changes were measured based on the 4D-CBCT of planning simulation, pre-, and post-SBRT. Significant inter- and intrafractional changes in liver tumor motion were defined as a change of >3 mm. The mean (± SD) liver tumor motion of the planning simulation 4D-CBCT was 1.7 ± 0.8 mm, 2.4 ± 2.2 mm, and 5.3 ± 3.3 mm, in the LR, AP, and SI directions, respectively. Those of the pre-SBRT 4D-CBCT were 1.2 ± 0.7 mm, 2.3 ± 2.3 mm, and 4.5 ± 3.8 mm, in the LR, AP, and SI directions, respectively. There was a strong significant correlation between liver tumor motion of the planning simulation and pre-SBRT in the LR (R = 0.7, P < 0.01), AP (R = 0.9, P < 0.01), and SI (R = 0.9, P < 0.01) directions. Significant inter- and intrafractional liver tumor motion changes occurred in 10 and 2% of treatment fractions, respectively. Liver tumor

  1. Histological advantages of the tumor graft: a murine model involving transplantation of human pancreatic cancer tissue fragments.

    PubMed

    Akashi, Yoshimasa; Oda, Tatsuya; Ohara, Yusuke; Miyamoto, Ryoichi; Hashimoto, Shinji; Enomoto, Tsuyoshi; Yamada, Keiichi; Kobayashi, Akihiko; Fukunaga, Kiyoshi; Ohkochi, Nobuhiro

    2013-11-01

    Experimental data based on cell line-derived xenograft models (cell xenograft) seldom reproduce the clinical situation, and therefore we demonstrated here the superiority of a murine model involving transplantation of human pancreatic cancer tissue fragments (tumor graft), focusing on the histological features and drug delivery characteristics. Tumor pieces from 10 pancreatic cancer patients were transplanted into SCID (severe combined immunodeficient) mice. Histological characteristics of tumor grafts, including morphology, desmoplastic reaction, and vascularization, were compared with those of cell xenografts. Drug delivery was evaluated by quantifying the concentrations of injected drug, and the results were compared with its histological features. Eight of the 10 transplanted tumors successfully engrafted. Histological comparisons between tumor grafts and cell xenografts revealed the following: the amount of stroma was more (22.9% ± 11.8% vs 10.8% ± 5.4%; P < 0.05), vessel-cancer cell distance was longer (35.3 ± 39.0 vs 3.9 ± 3.1 μm; P < 0.001), and microvessel density was lower (6.8 ± 1.9 vs 10.8 ± 2.1 vessels/0.4 mm(2); P < 0.05) in tumor grafts. Drug concentrations in tumor grafts were lower than those in cell xenografts (3.3 ± 1.2 vs 6.0±0.2 μg/mL; P = 0.003), and the differences were correlated with the histological differences. Pancreatic tumor grafts better reproduce the histological nature of clinical cancer and thus provide a more realistic model that is applicable for pharmacokinetic studies.

  2. MicroRNA-410 functions as a tumor suppressor by targeting angiotensin II type 1 receptor in pancreatic cancer.

    PubMed

    Guo, Rende; Gu, Jianhua; Zhang, Zhibin; Wang, Yi; Gu, Chuan

    2015-01-01

    MicroRNAs (miRNAs) act as key regulators of gene expression in diverse biological processes and are intimately involved in tumorigenesis. However, the underlying molecular mechanisms of miR-410 in pancreatic cancer remain poorly understood. In this study, we found that miR-410 overexpression suppressed pancreatic cancer cell growth in vitro and in vivo as well as cell invasion and migration. miR-410 also resulted in G1/S cell-cycle arrest. We then showed that angiotensin II type 1 receptor (AGTR1) was a direct target of miR-410, with miR-410 suppressing AGTR1 expression levels. In contrast, inhibition of miR-410 increased the expression of AGTR1. Silencing of AGTR1 inhibited cell growth and invasion, similar to miR-410 overexpression. In addition, we found that the induction of vascular endothelial growth factor and the activation of the ERK signaling pathway by angiotensin II were blocked by miR-410, similar to the angiotensin II inhibitor losartan. miR-410 overexpression inhibited angiogenesis in mice through the repression of CD31 expression. ERK pathway knockdown suppressed pancreatic cancer cell proliferation, invasion, and angiogenesis. Finally, we found that miR-410 was downregulated in pancreatic cancer tissues compared to adjacent nontumor tissues, whereas AGTR1 was upregulated in pancreatic cancer tissues. Pearson correlation analysis showed that miR-410 and AGTR1 were inversely expressed. In conclusion, our data indicate that miR-410 suppresses pancreatic cancer growth, cell invasion, migration, and angiogenesis via the downregulation of AGTR1, acting as a tumor-suppressive miRNA. In addition, our results suggest that miR-410 is a potential diagnostic biomarker and therapeutic target for patients with pancreatic cancer. © 2015 International Union of Biochemistry and Molecular Biology.

  3. Clinical Utility of Circulating Tumor DNA for Molecular Assessment and Precision Medicine in Pancreatic Cancer.

    PubMed

    Takai, Erina; Totoki, Yasushi; Nakamura, Hiromi; Kato, Mamoru; Shibata, Tatsuhiro; Yachida, Shinichi

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect molecular characteristics of tumors, supporting the concept of "liquid biopsy".We determined the mutational status of KRAS in plasma cfDNA using multiplex droplet digital PCR in 259 patients with PDAC, retrospectively. Furthermore, we constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA in 48 patients who had ≥1 % mutant allele frequencies of KRAS in plasma cfDNA.Droplet digital PCR detected KRAS mutations in plasma cfDNA in 63 of 107 (58.9 %) patients with inoperable tumors. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2 %) examined by cfDNA sequencing.Our two-step approach with plasma cfDNA, combining droplet digital PCR and targeted deep sequencing, is a feasible clinical approach. Assessment of mutations in plasma cfDNA may provide a new diagnostic tool, assisting decisions for optimal therapeutic strategies for PDAC patients.

  4. Risk Factors for Sporadic Pancreatic Neuroendocrine Tumors: A Case-Control Study

    PubMed Central

    Ben, Qiwen; Zhong, Jie; Fei, Jian; Chen, Haitao; Yv, Lifen; Tan, Jihong; Yuan, Yaozong

    2016-01-01

    The current study examined risk factors for sporadic pancreatic neuroendocrine tumors (PNETs), including smoking, alcohol use, first-degree family history of any cancer (FHC), and diabetes in the Han Chinese ethnic group. In this clinic-based case-control analysis on 385 patients with sporadic PNETs and 614 age- and sex-matched controls, we interviewed subjects using a specific questionnaire on demographics and potential risk factors. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs). No significant differences were found between patients and controls in terms of demographic variables. Most of the patients with PNETs had well-differentiated PNETs (G1, 62.9%) and non-advanced European Neuroendocrine Tumor Society (ENETS) stage (stage I or II, 83.9%). Ever/heavy smoking, a history of diabetes and a first-degree FHC were independent risk factors for non-functional PNETs. Only heavy drinking was found to be an independent risk factor for functional PNETs (AOR = 1.87; 95% confidence interval [CI], 1.01–3.51). Ever/heavy smoking was also associated with advanced ENETS staging (stage III or IV) at the time of diagnosis. This study identified first-degree FHC, ever/heavy smoking, and diabetes as risk factors for non-functional PNETs, while heavy drinking as a risk factor for functional PNETs. PMID:27782199

  5. Pancreatic neuroendocrine tumor and solid-pseudopapillary neoplasm: Key immunohistochemical profiles for differential diagnosis

    PubMed Central

    Ohara, Yusuke; Oda, Tatsuya; Hashimoto, Shinji; Akashi, Yoshimasa; Miyamoto, Ryoichi; Enomoto, Tsuyoshi; Satomi, Kaishi; Morishita, Yukio; Ohkohchi, Nobuhiro

    2016-01-01

    AIM To reveal better diagnostic markers for differentiating neuroendocrine tumor (NET) from solid-pseudopapillary neoplasm (SPN), focusing primarily on immunohistochemical analysis. METHODS We reviewed 30 pancreatic surgical specimens of NET (24 cases) and SPN (6 cases). We carried out comprehensive immunohistochemical profiling using 9 markers: Synaptophysin, chromogranin A, pan-cytokeratin, E-cadherin, progesterone receptor, vimentin, α-1-antitrypsin, CD10, and β-catenin. RESULTS E-cadherin staining in NETs, and nuclear labeling of β-catenin in SPNs were the most sensitive and specific markers. Dot-like staining of chromogranin A might indicate the possibility of SPNs rather than NETs. The other six markers were not useful because their expression overlapped widely between NETs and SPNs. Moreover, two cases that had been initially diagnosed as NETs on the basis of their morphological features, demonstrated SPN-like immunohistochemical profiles. Careful diagnosis is crucial as we actually found two confusing cases showing disagreement between the tumor morphology and immunohistochemical profiles. CONCLUSION E-cadherin, chromogranin A, and β-catenin were the most useful markers which should be employed for differentiating between NET and SPN. PMID:27784972

  6. Pancreatic neuroendocrine neoplasms at magnetic resonance imaging: comparison between grade 3 and grade 1/2 tumors

    PubMed Central

    Guo, Chuangen; Chen, Xiao; Xiao, Wenbo; Wang, Qidong; Sun, Ke; Wang, Zhongqiu

    2017-01-01

    Background The grading of pancreatic neuroendocrine neoplasms (PanNENs) is associated with the choice of treatment strategy. The aim of this study is to identify the magnetic resonance imaging (MRI) features in differentiating pancreatic neuroendocrine tumors (PanNETs) grade 1/2 (G1/G2) and pancreatic neuroendocrine carcinoma grade 3 (PanNEC G3). Patients and methods A total of 59 patients with histologically proven PanNENs and who underwent pretreatment MRI were retrospectively analyzed. Tumor location, size, boundary, cystic or solid appearance, enhancement degree, pancreatic duct dilatation, metastases and MRI signal were evaluated. Apparent diffusion coefficients (ADCs) were measured on ADC maps. Receiver operating characteristic curve was used to determine the cut off values and the sensitivity and specificity of prediction. Spearman correlation and logistic regression analysis were adopted to identify the association between MRI features and pathological parameters. Results A total of 47 lesions were PanNETs G1/G2 and 12 lesions were PanNEC G3. G1/G2 tumors were more common with well-circumscribed border compared with PanNEC G3. Ill- defined boundary, big size, necrosis, low-moderate enhancement, pancreatic duct dilatation, metastases and high diffusion-weighted imaging (DWI) intensity were more common in PanNEC G3 than in PanNETs G1/G2. The ADC values of PanNEC G3 were also significantly lower compared with the PanNETs G1/G2 and normal pancreatic parenchyma. The cut off value of ADC was 0.95×10−3 mm2/s for differentiating PanNEC G3 from PanNETs G1/G2 with 72.3% sensitivity and 91.6% specificity, respectively. Ki-67 index and mitosis count positively correlated with tumor size, pancreatic duct dilatation and metastases (P<0.05) and negatively correlated with ADC values (P<0.01), respectively. Regression analysis further showed that metastases and ADC value were associated with PanNENs grade. Conclusion Metastases and ADC value may have potential for

  7. Optimal surface marker locations for tumor motion estimation in lung cancer radiotherapy

    NASA Astrophysics Data System (ADS)

    Dong, Bin; Jiang Graves, Yan; Jia, Xun; Jiang, Steve B.

    2012-12-01

    Using fiducial markers on the patient’s body surface to predict the tumor location is a widely used approach in lung cancer radiotherapy. The purpose of this work is to propose an algorithm that automatically identifies a sparse set of locations on the patient’s surface with the optimal prediction power for the tumor motion. In our algorithm, it is assumed that there is a linear relationship between the surface marker motion and the tumor motion. The sparse selection of markers on the external surface and the linear relationship between the marker motion and the internal tumor motion are represented by a prediction matrix. Such a matrix is determined by solving an optimization problem, where the objective function contains a sparsity term that penalizes the number of markers chosen on the patient’s surface. Bregman iteration is used to solve the proposed optimization problem. The performance of our algorithm has been tested on realistic clinical data of four lung cancer patients. Thoracic 4DCT scans with ten phases are used for the study. On a reference phase, a grid of points are casted on the patient’s surfaces (except for the patient’s back) and propagated to other phases via deformable image registration of the corresponding CT images. Tumor locations at each phase are also manually delineated. We use nine out of ten phases of the 4DCT images to identify a small group of surface markers that are mostly correlated with the motion of the tumor and find the prediction matrix at the same time. The tenth phase is then used to test the accuracy of the prediction. It is found that on average six to seven surface markers are necessary to predict tumor locations with a 3D error of about 1 mm. It is also found that the selected marker locations lie closely in those areas where surface point motion has a large amplitude and a high correlation with the tumor motion. Our method can automatically select sparse locations on the patient’s external surface and

  8. MicroRNA-7 functions as a tumor-suppressor gene by regulating ILF2 in pancreatic carcinoma.

    PubMed

    Bi, Yiliang; Shen, Wei; Min, Min; Liu, Yan

    2017-04-01

    Interleukin enhancer binding factor 2 (ILF2) has been found to be markedly upregulated in pancreatic carcinoma and is involved in the pathogenesis of pancreatic carcinoma. Thus, ILF2 may be a potential target for therapy. Yet, the regulatory mechanisms of ILF2 in pancreatic carcinoma remain largely elusive. In the present study, we demonstrated that ILF2 functioned as an oncogene and regulated epithelial-mesenchymal transition (EMT)-associated genes in pancreatic carcinoma PANC-1 cells. MicroRNA-7 (miR-7) suppressed ILF2 mRNA expression and the protein level in PANC-1 cells. Contrary to ILF2, miRNA-7 functioned as a tumor-suppressor gene and negatively regulated EMT-associated genes in the PANC-1 cells. Curcumin, a polyphenol natural product isolated from the rhizome of the plant Curcuma longa, has emerged as a promising anticancer therapeutic agent. We found that treatment with curcumin increased miR-7 expression and suppressed ILF2 protein in the PANC-1 cells. Thus, we identified ILF2 as a new downstream target gene of curcumin. The results revealed that ILF2 is regulated by miR-7 and suggest that downregulation of miR-7 may be an important factor for the ILF2 overexpression in pancreatic carcinoma.

  9. MicroRNA-7 functions as a tumor-suppressor gene by regulating ILF2 in pancreatic carcinoma

    PubMed Central

    Bi, Yiliang; Shen, Wei; Min, Min; Liu, Yan

    2017-01-01

    Interleukin enhancer binding factor 2 (ILF2) has been found to be markedly upregulated in pancreatic carcinoma and is involved in the pathogenesis of pancreatic carcinoma. Thus, ILF2 may be a potential target for therapy. Yet, the regulatory mechanisms of ILF2 in pancreatic carcinoma remain largely elusive. In the present study, we demonstrated that ILF2 functioned as an oncogene and regulated epithelial-mesenchymal transition (EMT)-associated genes in pancreatic carcinoma PANC-1 cells. MicroRNA-7 (miR-7) suppressed ILF2 mRNA expression and the protein level in PANC-1 cells. Contrary to ILF2, miRNA-7 functioned as a tumor-suppressor gene and negatively regulated EMT-associated genes in the PANC-1 cells. Curcumin, a polyphenol natural product isolated from the rhizome of the plant Curcuma longa, has emerged as a promising anticancer therapeutic agent. We found that treatment with curcumin increased miR-7 expression and suppressed ILF2 protein in the PANC-1 cells. Thus, we identified ILF2 as a new downstream target gene of curcumin. The results revealed that ILF2 is regulated by miR-7 and suggest that downregulation of miR-7 may be an important factor for the ILF2 overexpression in pancreatic carcinoma. PMID:28259961

  10. TRA-8 anti-DR5 monoclonal antibody and gemcitabine induce apoptosis and inhibit radiologically validated orthotopic pancreatic tumor growth.

    PubMed

    Derosier, Leo Christopher; Vickers, Selwyn M; Zinn, Kurt R; Huang, Zhi; Wang, Wenquan; Grizzle, William E; Sellers, Jeffrey; Stockard, Cecil R; Zhou, Tong; Oliver, Patsy G; Arnoletti, Pablo; Lobuglio, Albert F; Buchsbaum, Donald J

    2007-12-01

    To evaluate agonistic TRA-8 monoclonal antibody to human death receptor 5 (DR5) and gemcitabine in vitro and in an orthotopic pancreatic cancer model. Pancreatic cancer cell lines were screened for DR5 expression, cytotoxicity, and apoptosis induced by TRA-8, gemcitabine, or gemcitabine and TRA-8. An orthotopic model of pancreatic cancer was established in severe combined immunodeficient mice. Mice were treated with TRA-8, gemcitabine, or a combination for one or two cycles of therapy. Tumor growth (ultrasound) and survival were analyzed. All five pancreatic cancer cell lines showed DR5 protein expression and varying sensitivity to TRA-8-mediated cytotoxicity. MIA PaCa-2 cells were very sensitive to TRA-8, moderately resistant to gemcitabine, with additive cytotoxicity to the combination. S2-VP10 cells were resistant to TRA-8 and sensitive to gemcitabine with synergistic sensitivity to the combination. Combination treatment in vitro produced enhanced caspase-3 and caspase-8 activation. A single cycle of therapy produced comparable efficacy for single-agent TRA-8 and the combination of TRA-8 and gemcitabine, with significant reduction in tumor size and prolonged survival compared with gemcitabine alone or control animals. With two cycles of therapy, TRA-8 and combination therapy produced enhanced inhibition of tumor growth compared with single-agent gemcitabine or untreated animals. However, the combination regimen showed enhanced survival as compared with single-agent TRA-8. Pancreatic cancer cell lines express varying levels of DR5 and differ in their sensitivity to TRA-8 and gemcitabine-induced cytotoxicity. TRA-8 with two cycles of gemcitabine therapy produced the best overall survival.

  11. Laparoscopic versus open distal pancreatectomy for nonfunctioning pancreatic neuroendocrine tumors: a large single-center study.

    PubMed

    Han, Sang Hyup; Han, In Woong; Heo, Jin Seok; Choi, Seong Ho; Choi, Dong Wook; Han, Sunjong; You, Yung Hun

    2017-06-29

    Pancreatic neuroendocrine tumors (PNETs) account for 1-2% of all pancreatic neoplasms. Nonfunctioning PNETs (NF-PNETs) account for 60-90% of all PNETs. Laparoscopic distal pancreatectomy (LDP) is becoming the treatment of choice for benign lesions in the body and tail of the pancreas. However, LDP has not yet been widely accepted as the gold standard for NF-PNETs. The purpose of this study is to evaluate the clinical and oncologic outcomes after laparoscopic versus open distal pancreatectomy (ODP) for NF-PNETs. Between April 1995 and September 2016, 94 patients with NF-PNETs underwent open or laparoscopic distal pancreatectomy at Samsung Medical Center. Patients were divided into two groups: those who underwent LDP and those who underwent ODP. Both groups were compared in terms of clinical and oncologic variables. LDP patients had a significantly shorter hospital stay compared with ODP patients, amounting to a mean difference of 2 days (p < 0.001). Overall complication rates did not differ significantly between the ODP and LDP groups (p = 0.379). The 3-year overall survival rates in the ODP and LDP groups were 93.7 and 100%, respectively (p = 0.069). In this study, LDP for NF-PNETs had similar oncologic outcomes compared with ODP. In addition, LDP was associated with a shorter hospital stay compared with ODP. Therefore, LDP is a safe and effective procedure for patients with NF-PNETs. A multicenter study and a randomized controlled trial are needed to better assess the clinical and oncologic outcomes.

  12. The expression of FOXL2 in pancreatic, hepatobiliary, and renal tumors with ovarian-type stroma.

    PubMed

    Westerhoff, Maria; Tretiakova, Maria; Hart, John; Gwin, Katja; Liu, Xiuli; Zhou, Ming; Yeh, Matthew M; Antic, Tatjana

    2014-05-01

    FOXL2, a gene encoding a member of the fork-head-winged-helix family of transcription factors, is one of the earliest expressed genes during female gonadal development. It is expressed in normal ovarian stroma and ovarian neoplasms with granulosa cell lineage. Nonovarian tumors such as pancreatic mucinous cystic neoplasms (PMCs), hepatobiliary cystadenomas (HBCs), and mixed epithelial and stromal tumor of the kidney (MEST) have ovarian-type stroma. Immunohistochemical staining with FOXL2, estrogen receptor, and progesterone receptor was performed on 21 PMCs, 13 HBCs, and 10 MESTs and assessed for nuclear immunohistochemical positivity in the tumor stroma. All cases of PMC and HBC demonstrated nuclear reactivity for FOXL2 in the subepithelial stromal cells. Ninety percent of MEST demonstrated nuclear FOXL2 positivity. Estrogen receptor nuclear positivity was demonstrated in 57% of PMC, 77% of HBC, and 80% of MEST. Progesterone receptor nuclear positivity was present in 67% of PMC, 100% of HBC, and 90% of MEST. Clinical information was available for 37 patients. Seventy-eight percent of the patients had a history of obesity, heavy alcohol use, or hormone-related therapy. The 2 male patients had histories significant for morbid obesity and chronic alcoholism. FOXL2 is expressed from the early stages of ovarian development and has been shown to be mandatory for normal ovarian function. We have shown that it is also expressed in the aberrant ovarian-type stroma characteristic of PMC, HBC, and MEST. Most of such patients, including the rare male patients, have risk factors for hormonal abnormalities such as obesity and hormonal replacement therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Aminoguanidine impedes human pancreatic tumor growth and metastasis development in nude mice.

    PubMed

    Mohamad, Nora A; Cricco, Graciela P; Sambuco, Lorena A; Croci, Máximo; Medina, Vanina A; Gutiérrez, Alicia S; Bergoc, Rosa M; Rivera, Elena S; Martín, Gabriela A

    2009-03-07

    To study the action of aminoguanidine on pancreatic cancer xenografts in relation to cell proliferation, apoptosis, redox status and vascularization. Xenografts of PANC-1 cells were developed in nude mice. The animals were separated into two groups: control and aminoguanidine treated. Tumor growth, survival and appearance of metastases were determined in vivo in both groups. Tumors were excised and ex vivo histochemical studies were performed. Cell growth was assessed by Ki-67 expression. Apoptosis was studied by intratumoral expression of B cell lymphoma-2 protein (Bcl-2) family proteins and Terminal deoxynucleotidyl transferase biotin-dUTP Nick End Labeling (Tunel). Redox status was evaluated by the expression of endothelial nitric oxide synthase (eNOS), catalase, copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx). Finally, vascularization was determined by Massons trichromic staining, and by VEGF and CD34 expression. Tumor volumes after 32 d of treatment by aminoguanidine (AG) were significantly lower than in control mice (P < 0.01). Median survival of AG mice was significantly greater than control animals (P < 0.01). The appearance of both homolateral and contralateral palpable metastases was significantly delayed in AG group. Apoptotic cells, intratumoral vascularization (trichromic stain) and the expression of Ki-67, Bax, eNOS, CD34, VEGF, catalase, CuZnSOD and MnSOD were diminished in AG treated mice (P < 0.01), while the expression of Bcl-2 and GPx did not change. The antitumoral action of aminoguanidine is associated with decreased cell proliferation, reduced angiogenesis, and reduced expression of antioxidant enzymes.

  14. Genetic deletion of the desmosomal component desmoplakin promotes tumor microinvasion in a mouse model of pancreatic neuroendocrine carcinogenesis.

    PubMed

    Chun, Matthew G H; Hanahan, Douglas

    2010-09-16

    We used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to profile the transcriptome of pancreatic neuroendocrine tumors (PNET) that were either non-invasive or highly invasive, seeking to identify pro- and anti-invasive molecules. Expression of multiple components of desmosomes, structures that help maintain cellular adhesion, was significantly reduced in invasive carcinomas. Genetic deletion of one of these desmosomal components, desmoplakin, resulted in increased local tumor invasion without affecting tumor growth parameters in RT2 PNETs. Expression of cadherin 1, a component of the adherens junction adhesion complex, was maintained in these tumors despite the genetic deletion of desmoplakin. Our results demonstrate that loss of desmoplakin expression and resultant disruption of desmosomal adhesion can promote increased local tumor invasion independent of adherens junction status.

  15. Sequential treatment in disseminated well- and intermediate-differentiated pancreatic neuroendocrine tumors: Common sense or low rationale?

    PubMed

    Grande, Enrique

    2016-04-10

    Fortunately, the landscape of the systemic treatment for grade 1 and 2 pancreatic neuroendocrine tumors has changed in the last decade with at least four different alternatives approved in the field. Chemotherapy, somatostatin analogues, sunitinib and everolimus remind valid options according to the most referenced international guidelines. However, and although this is something done in the routine practice, there is a lack of evidence for the use of any of these strategies after failure to the others. Moreover, further sequential alternatives in third or fourth line have never been tested prospectively. The need for a better understanding of the rationale to sequence different systemic options is even greater in non-pancreatic neuroendocrine tumors since available therapies are scarce. Sequential strategies in other solid tumors have led to a clear improvement in overall survival. This is also believed to occur in neuroendocrine tumors but no clear data on it has been delivered yet. We postulate that the different mode of action of the systemic options available for the treatment of neuroendocrine tumors may avoid the complete resistance of one option after the other and that sequential use of these agents will be translated into a longer overall survival of patients. Prospective and randomized trials that seek for the activity of drugs after failure to another systemic alternatives are highly needed in this field of neuroendocrine tumors.

  16. Extracellular matrix composition and rigidity regulate invasive behavior and response to PDT in 3D pancreatic tumor models

    NASA Astrophysics Data System (ADS)

    Cramer, Gwendolyn; El-Hamidi, Hamid; Jafari, Seyedehrojin; Jones, Dustin P.; Celli, Jonathan P.

    2016-03-01

    The composition and mechanical compliance of the extracellular matrix (ECM) have been shown to serve as regulators of tumor growth and invasive behavior. These effects may be particularly relevant in tumors of the pancreas, noted for a profound desmoplastic reaction and an abundance of stroma rich in ECM. In view of recent progress in the clinical implementation of photodynamic therapy (PDT) for pancreatic tumors, in this report we examine how ECM composition and rheological properties impact upon invasive behavior and response to PDT in 3D multicellular pancreatic tumor spheroids in ECM environments with characterized rheological properties. Tumor spheroids were cultured initially in attachment-free conditions to form millimeter-sized spheroids that were transplanted into reconstituted ECM microenvironments (Matrigel and Type I Collagen) that were characterized using bulk oscillatory shear rheology. Analysis of growth behavior shows that the soft collagen ECM promoted growth and extensive invasion and this microenvironment was used in subsequent assessment of PDT and chemotherapy response. Evaluation of treatment response revealed that primary tumor nodule growth is inhibited more effectively with PDT, while verteporfin PDT response is significantly enhanced in the ECM-infiltrating populations that are non-responsive to oxaliplatin chemotherapy. This finding is potentially significant, suggesting the potential for PDT to target these clinically problematic invasive populations that are associated with aggressive metastatic progression and chemoresistance. Experiments to further validate and identify the mechanistic basis of this observation are ongoing.

  17. Dosimetric evaluation of intrafractional tumor motion by means of a robot driven phantom.

    PubMed

    Richter, Anne; Wilbert, Jurgen; Flentje, Michael

    2011-10-01

    The aim of the work was to investigate the influence of intrafractional tumor motion to the accumulated (absorbed) dose. The accumulated dose was determined by means of calculations and measurements with a robot driven motion phantom. Different motion scenarios and compensation techniques were realized in a phantom study to investigate the influence of motion on image acquisition, dose calculation, and dose measurement. The influence of motion on the accumulated dose was calculated by employing two methods (a model based and a voxel based method). Tumor motion resulted in a blurring of steep dose gradients and a reduction of dose at the periphery of the target. A systematic variation of motion parameters allowed the determination of the main influence parameters on the accumulated dose. The key parameters with the greatest influence on dose were the mean amplitude and the pattern of motion. Investigations on necessary safety margins to compensate for dose reduction have shown that smaller safety margins are sufficient, if the developed concept with optimized margins (OPT concept) was used instead of the standard internal target volume (ITV) concept. Both calculation methods were a reasonable approximation of the measured dose with the voxel based method being in better agreement with the measurements. Further evaluation of available systems and algorithms for dose accumulation are needed to create guidelines for the verification of the accumulated dose.

  18. Dosimetric evaluation of intrafractional tumor motion by means of a robot driven phantom

    SciTech Connect

    Richter, Anne; Wilbert, Juergen; Flentje, Michael

    2011-10-15

    Purpose: The aim of the work was to investigate the influence of intrafractional tumor motion to the accumulated (absorbed) dose. The accumulated dose was determined by means of calculations and measurements with a robot driven motion phantom. Methods: Different motion scenarios and compensation techniques were realized in a phantom study to investigate the influence of motion on image acquisition, dose calculation, and dose measurement. The influence of motion on the accumulated dose was calculated by employing two methods (a model based and a voxel based method). Results: Tumor motion resulted in a blurring of steep dose gradients and a reduction of dose at the periphery of the target. A systematic variation of motion parameters allowed the determination of the main influence parameters on the accumulated dose. The key parameters with the greatest influence on dose were the mean amplitude and the pattern of motion. Investigations on necessary safety margins to compensate for dose reduction have shown that smaller safety margins are sufficient, if the developed concept with optimized margins (OPT concept) was used instead of the standard internal target volume (ITV) concept. Both calculation methods were a reasonable approximation of the measured dose with the voxel based method being in better agreement with the measurements. Conclusions: Further evaluation of available systems and algorithms for dose accumulation are needed to create guidelines for the verification of the accumulated dose.

  19. Risk factors for aggressive nonfunctional pancreatic neuroendocrine tumors and the role of endoscopic ultrasound guided fine-needle aspiration

    PubMed Central

    Ende, Alexander R.; Sedarat, Alireza; Shah, Pari; Jhala, Nirag; Fraker, Douglas L.; Drebin, Jeffrey A.; Metz, David C.; Kochman, Michael L.

    2016-01-01

    Background: Nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) are increasingly being diagnosed but management, especially of small tumors, remains a clinical dilemma. Endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) is now routinely used for diagnosis of pancreatic neuroendocrine tumors (pNETs) but has not been well studied as a tool for identifying aggressive disease. Materials and Methods: A systematic search of the cytology database identified all patients at our center who underwent EUS-FNA from 1999 through 2011 and were diagnosed with NF-pNET. Results: A total of 50 patients were identified. Though patients with metastatic disease had a mean tumor size of 40 mm compared to 25 mm in patients without metastatic disease (P = 0.04), we also identified several patients with tumors <20 mm who presented with metastatic disease. Furthermore, we found no statistically significant difference in metastatic disease between tumors <20 mm and >20 mm (P = 0.13). Using receiver operating characteristic (ROC) analysis, we found that using a cutoff point of 20 mm only led to a sensitivity of 85% in screening for metastases, while lowering the cutoff point to 18 mm allowed for a sensitivity of 95%. Conclusion: Currently, guidelines suggest that only patients with tumors greater than 20 mm undergo surgical resection, as tumors less than this size are thought to have low risk of metastases. Our analysis suggests that these recommendations could lead to undertreating patients with small tumors. Tumor size alone may be inadequate as a marker for aggressive NF-pNETs. Given this, other risk factors for aggressive pNETs should be studied to help identify the patients most likely to benefit from surgery. PMID:26879167

  20. Multiple KRAS mutations in pancreatic adenocarcinoma: molecular features of neoplastic clones indicate the selection of divergent populations of tumor cells.

    PubMed

    Visani, Michela; de Biase, Dario; Baccarini, Paola; Fabbri, Carlo; Polifemo, Anna Maria; Zanini, Nicola; Pession, Annalisa; Tallini, Giovanni

    2013-12-01

    KRAS is one of the most common genes mutated in pancreatic adenocarcinoma. Multiple KRAS mutations may be detected within the same pancreatic adenocarcinoma, but it is usually unclear whether the different mutations represent biologically irrelevant molecular events or whether they indicate the coexistence of distinct sizable neoplastic clones within a given tumor. We identified a case of pancreatic adenocarcinoma with 5 different mutations in the KRAS gene and have been able to characterize the allelic distribution of the KRAS mutations and the size of the neoplastic clones using allele-specific locked nucleic acid polymerase chain reaction and next-generation sequencing (454 GS-Junior). The results indicate that the tumor is composed of 5 distinct cell populations: one is KRAS G12V mutated (~38% of neoplastic cells), the second is KRAS G12V in one allele and KRAS G12D in the other (~32%), the third is KRAS G12V in one allele and KRAS G12R in the other (~24%), and the fourth is KRAS G12V in one allele and KRAS G12C in the other (~6%). The fifth clone, representing a minority of neoplastic cells, has a KRAS Q61H mutation in addition to one of the above alterations. Microsatellite analysis identified mutation of the NR21 marker out of the 13 tested, indicating that the tumor has a defect in maintaining DNA integrity different from loss of conventional DNA mismatch repair. These results are consistent with the successive selection of divergent populations of tumor cells and underscore the relevance of nucleotide instability in pancreatic adenocarcinoma.

  1. IGRT/ART phantom with programmable independent rib cage and tumor motion

    SciTech Connect

    Haas, Olivier C. L.; Mills, John A.; Land, Imke; Mulholl, Pete; Menary, Paul; Crichton, Robert; Wilson, Adrian; Sage, John; Anna, Morenc; Depuydt, Tom

    2014-02-15

    Purpose: This paper describes the design and experimental evaluation of the Methods and Advanced Equipment for Simulation and Treatment in Radiation Oncology (MAESTRO) thorax phantom, a new anthropomorphic moving ribcage combined with a 3D tumor positioning system to move target inserts within static lungs. Methods: The new rib cage design is described and its motion is evaluated using Vicon Nexus, a commercial 3D motion tracking system. CT studies at inhale and exhale position are used to study the effect of rib motion and tissue equivalence. Results: The 3D target positioning system and the rib cage have millimetre accuracy. Each axis of motion can reproduce given trajectories from files or individually programmed sinusoidal motion in terms of amplitude, period, and phase shift. The maximum rib motion ranges from 7 to 20 mm SI and from 0.3 to 3.7 mm AP with LR motion less than 1 mm. The repeatability between cycles is within 0.16 mm root mean square error. The agreement between CT electron and mass density for skin, ribcage, spine hard and inner bone as well as cartilage is within 3%. Conclusions: The MAESTRO phantom is a useful research tool that produces programmable 3D rib motions which can be synchronized with 3D internal target motion. The easily accessible static lungs enable the use of a wide range of inserts or can be filled with lung tissue equivalent and deformed using the target motion system.

  2. IGRT/ART phantom with programmable independent rib cage and tumor motion

    SciTech Connect

    Haas, Olivier C. L.; Mills, John A.; Land, Imke; Mulholl, Pete; Menary, Paul; Crichton, Robert; Wilson, Adrian; Sage, John; Anna, Morenc; Depuydt, Tom

    2014-02-15

    Purpose: This paper describes the design and experimental evaluation of the Methods and Advanced Equipment for Simulation and Treatment in Radiation Oncology (MAESTRO) thorax phantom, a new anthropomorphic moving ribcage combined with a 3D tumor positioning system to move target inserts within static lungs. Methods: The new rib cage design is described and its motion is evaluated using Vicon Nexus, a commercial 3D motion tracking system. CT studies at inhale and exhale position are used to study the effect of rib motion and tissue equivalence. Results: The 3D target positioning system and the rib cage have millimetre accuracy. Each axis of motion can reproduce given trajectories from files or individually programmed sinusoidal motion in terms of amplitude, period, and phase shift. The maximum rib motion ranges from 7 to 20 mm SI and from 0.3 to 3.7 mm AP with LR motion less than 1 mm. The repeatability between cycles is within 0.16 mm root mean square error. The agreement between CT electron and mass density for skin, ribcage, spine hard and inner bone as well as cartilage is within 3%. Conclusions: The MAESTRO phantom is a useful research tool that produces programmable 3D rib motions which can be synchronized with 3D internal target motion. The easily accessible static lungs enable the use of a wide range of inserts or can be filled with lung tissue equivalent and deformed using the target motion system.

  3. Sensitivity of Tumor Motion Simulation Accuracy to Lung Biomechanical Modeling Approaches and Parameters

    PubMed Central

    Tehrani, Joubin Nasehi; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu

    2015-01-01

    Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the Neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation. PMID:26531324

  4. Sensitivity of tumor motion simulation accuracy to lung biomechanical modeling approaches and parameters.

    PubMed

    Tehrani, Joubin Nasehi; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu; Wang, Jing

    2015-11-21

    Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right, anterior-posterior, and superior-inferior directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation.

  5. Sensitivity of tumor motion simulation accuracy to lung biomechanical modeling approaches and parameters

    NASA Astrophysics Data System (ADS)

    Nasehi Tehrani, Joubin; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu; Wang, Jing

    2015-11-01

    Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right, anterior-posterior, and superior-inferior directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation.

  6. Downregulation of Human Endogenous Retrovirus Type K (HERV-K) Viral env RNA in Pancreatic Cancer Cells Decreases Cell Proliferation and Tumor Growth.

    PubMed

    Li, Ming; Radvanyi, Laszlo; Yin, Bingnan; Li, Jia; Chivukula, Raghavender; Lin, Kevin; Lu, Yue; Shen, JianJun; Chang, David Z; Li, Donghui; Johanning, Gary L; Wang-Johanning, Feng

    2017-10-01

    Purpose: We investigated the role of the human endogenous retrovirus type K (HERV-K) envelope (env) gene in pancreatic cancer.Experimental Design: shRNA was employed to knockdown (KD) the expression of HERV-K in pancreatic cancer cells.Results: HERV-K env expression was detected in seven pancreatic cancer cell lines and in 80% of pancreatic cancer patient biopsies, but not in two normal pancreatic cell lines or uninvolved normal tissues. A new HERV-K splice variant was discovered in several pancreatic cancer cell lines. Reverse transcriptase activity and virus-like particles were observed in culture media supernatant obtained from Panc-1 and Panc-2 cells. HERV-K viral RNA levels and anti-HERV-K antibody titers were significantly higher in pancreatic cancer patient sera (N = 106) than in normal donor sera (N = 40). Importantly, the in vitro and in vivo growth rates of three pancreatic cancer cell lines were significantly reduced after HERV-K KD by shRNA targeting HERV-K env, and there was reduced metastasis to lung after treatment. RNA-Seq results revealed changes in gene expression after HERV-K env KD, including RAS and TP53. Furthermore, downregulation of HERV-K Env protein expression by shRNA also resulted in decreased expression of RAS, p-ERK, p-RSK, and p-AKT in several pancreatic cancer cells or tumors.Conclusions: These results demonstrate that HERV-K influences signal transduction via the RAS-ERK-RSK pathway in pancreatic cancer. Our data highlight the potentially important role of HERV-K in tumorigenesis and progression of pancreatic cancer, and indicate that HERV-K viral proteins may be attractive biomarkers and/or tumor-associated antigens, as well as potentially useful targets for detection, diagnosis, and immunotherapy of pancreatic cancer. Clin Cancer Res; 23(19); 5892-911. ©2017 AACR. ©2017 American Association for Cancer Research.

  7. Extraction of tumor motion trajectories using PICCS-4DCBCT: A validation study

    SciTech Connect

    Qi Zhihua; Chen Guanghong

    2011-10-15

    Purpose: As a counterpart of 4DCT in the treatment planning stage of radiotherapy treatment, 4D cone beam computed tomography (4DCBCT) method has been proposed to verify tumor motion trajectories before radiation therapy treatment delivery. Besides 4DCBCT acquisition using slower gantry rotation speed or multiple rotations, a new method using the prior image constrained compressed sensing (PICCS) image reconstruction method and the standard 1-min data acquisition were proposed. In this paper, the PICCS-4DCBCT method was combined with deformable registration to validate its capability in motion trajectory extraction using physical phantom data, simulated human subject data from 4DCT and in vivo human subject data. Methods: Two methods were used to validate PICCS-4DCBCT for the purpose of respiratory motion delineation. The standard 1-min gantry rotation Cone Beam CT acquisition was used for both methods. In the first method, 4DCBCT projection data of a physical motion phantom were acquired using an on-board CBCT acquisition system (Varian Medical Systems, Palo Alto, CA). Using a deformable registration method, the object motion trajectories were extracted from both FBP and PICCS reconstructed 4DCBCT images, and compared against the programmed motion trajectories. In the second method, using a clinical 4DCT dataset, Cone Beam CT projections were simulated by forward projection. Using a deformable registration method, the tumor motion trajectories were extracted from the reconstructed 4DCT and PICCS-4DCBCT images. The performance of PICCS-4DCBCT is assessed against the 4DCT ground truth. The breathing period was varied in the simulation to study its effect on motion extraction. For both validation methods, the root mean square error (RMSE) and the maximum of the errors (MaxE) were used to quantify the accuracy of the extracted motion trajectories. After the validation, a clinical dataset was used to demonstrate the motion delineation capability of PICCS-4DCBCT for

  8. Extraction of tumor motion trajectories using PICCS-4DCBCT: A validation study

    PubMed Central

    Qi, Zhihua; Chen, Guang-Hong

    2011-01-01

    Purpose: As a counterpart of 4DCT in the treatment planning stage of radiotherapy treatment, 4D cone beam computed tomography (4DCBCT) method has been proposed to verify tumor motion trajectories before radiation therapy treatment delivery. Besides 4DCBCT acquisition using slower gantry rotation speed or multiple rotations, a new method using the prior image constrained compressed sensing (PICCS) image reconstruction method and the standard 1-min data acquisition were proposed. In this paper, the PICCS-4DCBCT method was combined with deformable registration to validate its capability in motion trajectory extraction using physical phantom data, simulated human subject data from 4DCT and in vivo human subject data. Methods: Two methods were used to validate PICCS-4DCBCT for the purpose of respiratory motion delineation. The standard 1-min gantry rotation Cone Beam CT acquisition was used for both methods. In the first method, 4DCBCT projection data of a physical motion phantom were acquired using an on-board CBCT acquisition system (Varian Medical Systems, Palo Alto, CA). Using a deformable registration method, the object motion trajectories were extracted from both FBP and PICCS reconstructed 4DCBCT images, and compared against the programmed motion trajectories. In the second method, using a clinical 4DCT dataset, Cone Beam CT projections were simulated by forward projection. Using a deformable registration method, the tumor motion trajectories were extracted from the reconstructed 4DCT and PICCS-4DCBCT images. The performance of PICCS-4DCBCT is assessed against the 4DCT ground truth. The breathing period was varied in the simulation to study its effect on motion extraction. For both validation methods, the root mean square error (RMSE) and the maximum of the errors (MaxE) were used to quantify the accuracy of the extracted motion trajectories. After the validation, a clinical dataset was used to demonstrate the motion delineation capability of PICCS-4DCBCT for

  9. Obesity, pancreatitis, and pancreatic cancer.

    PubMed

    Gumbs, Andrew A

    2008-09-01

    The only universally accepted risk factors for the development of pancreatic cancer are a positive family history or a history of smoking. Although the contribution of pancreatitis to pancreatic carcinogenesis has been debated for decades in the epidemiology literature, the actual mechanism is still unclear. With the rising epidemic of obesity, scientists have begun to focus on the contribution of chronic inflammatory state of morbidly obese patients in an effort to better understand the contribution of inflammation to the comorbidities of obesity. Notably, population studies are beginning to show that one of the most serious potential comorbidities of obesity is an increased lifetime risk of developing cancer. In this article, the current literature that exists supporting this Chronic Inflammatory Hypothesis as it pertains to obesity and pancreatic carcinogenesis is reviewed. To date, studies have focused on interleukin-6, a cytokine known to play a role in obesity, chronic pancreatitis and pancreatic cancer. The anti-inflammatory adipocytokine, adiponectin, has also shown promise as a key player in this mechanism and has recently been found to be more specific than standard tumor markers in differentiating pancreatic cancer from chronic pancreatitis. If the pathogenesis of pancreatic cancer is related to hormone levels associated with obesity, such as adipocytokines, and cytokines associated with chronic inflammation, this could potentially lead to the development of new pancreatic cancer tumor markers and ultimately new therapies and methods of prevention.

  10. Planning 4-Dimensional Computed Tomography (4DCT) Cannot Adequately Represent Daily Intrafractional Motion of Abdominal Tumors

    SciTech Connect

    Ge, Jiajia; Santanam, Lakshmi; Noel, Camille; Parikh, Parag J.

    2013-03-15

    Purpose: To evaluate whether planning 4-dimensional computed tomography (4DCT) can adequately represent daily motion of abdominal tumors in regularly fractionated and stereotactic body radiation therapy (SBRT) patients. Methods and Materials: Intrafractional tumor motion of 10 patients with abdominal tumors (4 pancreas-fractionated and 6 liver-stereotactic patients) with implanted fiducials was measured based on daily orthogonal fluoroscopic movies over 38 treatment fractions. The needed internal margin for at least 90% of tumor coverage was calculated based on a 95th and fifth percentile of daily 3-dimensional tumor motion. The planning internal margin was generated by fusing 4DCT motion from all phase bins. The disagreement between needed and planning internal margin was analyzed fraction by fraction in 3 motion axes (superior-inferior [SI], anterior-posterior [AP], and left-right [LR]). The 4DCT margin was considered as an overestimation/underestimation of daily motion when disagreement exceeded at least 3 mm in the SI axis and/or 1.2 mm in the AP and LR axes (4DCT image resolution). The underlying reasons for this disagreement were evaluated based on interfractional and intrafractional breathing variation. Results: The 4DCT overestimated daily 3-dimensional motion in 39% of the fractions in 7 of 10 patients and underestimated it in 53% of the fractions in 8 of 10 patients. Median underestimation was 3.9 mm, 3.0 mm, and 1.7 mm in the SI axis, AP axis, and LR axis, respectively. The 4DCT was found to capture irregular deep breaths in 3 of 10 patients, with 4DCT motion larger than mean daily amplitude by 18 to 21 mm. The breathing pattern varied from breath to breath and day to day. The intrafractional variation of amplitude was significantly larger than intrafractional variation (2.7 mm vs 1.3 mm) in the primary motion axis (ie, SI axis). The SBRT patients showed significantly larger intrafractional amplitude variation than fractionated patients (3.0 mm vs 2

  11. Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia

    PubMed Central

    Suklabaidya, Sujit; Das, Biswajit; Ali, Syed Azmal; Jain, Sumeet; Swaminathan, Sharada; Mohanty, Ashok K.; Panda, Susen K.; Dash, Pujarini; Chakraborty, Subhankar; Batra, Surinder K.; Senapati, Shantibhusan

    2016-01-01

    Desmoplasia in human pancreatic cancer (PC) promotes cancer progression and hinders effective drug delivery. The objectives of this study were to characterize a homologous orthotopic model of PC in Syrian golden hamster and investigate the effect of anti-fibrotic (pirfenidone), antioxidant (N-acetyl cysteine, NAC) and anti-addiction (disulfiram, DSF) drugs on desmoplasia and tumor growth in this model. The HapT1 PC cells when implanted orthotopically into hamsters formed tumors with morphological, cellular and molecular similarities to human PC. Protein profiling of activated hamster pancreatic stellate cells (ha-PSCs) revealed expression of proteins involved in fibrosis, cancer cells growth and metastasis. Pirfenidone, suppressed growth of HapT1 cells and the desmoplastic response in vivo; these effects were enhanced by co-administration of NAC. Disulfiram alone or in combination with copper (Cu) was toxic to HapT1 cells and PSCs in vitro; but co-administration of DSF and Cu accelerated growth of HapT1 cells in vivo. Moreover, DSF had no effect on tumor-associated desmoplasia. Overall, this study identifies HapT1-derived orthotopic tumors as a useful model to study desmoplasia and tumor-directed therapeutics in PC. Pirfenidone in combination with NAC could be a novel combination therapy for PC and warrants investigation in human subjects. PMID:27259232

  12. Salmonella-Based Therapy Targeting Indoleamine 2,3-Dioxygenase Coupled with Enzymatic Depletion of Tumor Hyaluronan Induces Complete Regression of Aggressive Pancreatic Tumors

    PubMed Central

    Manuel, Edwin R.; Chen, Jeremy; D'Apuzzo, Massimo; Lampa, Melanie G.; Kaltcheva, Teodora I.; Thompson, Curtis B.; Ludwig, Thomas; Chung, Vincent; Diamond, Don J.

    2015-01-01

    Bacterial-based therapies are emerging as effective cancer treatments and hold promise for refractory neoplasms such as pancreatic ductal adenocarcinoma (PDAC), which has not shown significant improvement in therapy for over twenty-five years. Using a novel combination of shIDO-ST, a Salmonella-based therapy targeting the immunosuppressive molecule indoleamine 2,3-dioxygenase (IDO), with an enzyme, PEGPH20, which depletes extracellular matrix hyaluronan, we observed extended survival with frequent total regression of autochthonous and orthotopic PDAC tumors. This was associated with migration and accumulation of activated polymorphonuclear neutrophils (PMN) from spleens into tumors, which was not observed using a scrambled control (shScr-ST). Purified splenic PMNs from PEGPH20/shIDO-ST-treated mice exhibited significant IDO knockdown and were able to kill tumor targets ex-vivo through mechanisms involving FasL and serine proteases. In addition, CD8+ T cells were observed to contribute to late control of pancreatic tumors. Collectively, our data demonstrate that entry of shIDO-ST and PMNs into otherwise impermeable desmoplastic tumors is facilitated by PEGPH20-mediated HA removal, further highlighting an important component of effective treatment for PDAC. PMID:26134178

  13. Evaluation of lung tumor motion management in radiation therapy with dynamic MRI

    NASA Astrophysics Data System (ADS)

    Park, Seyoun; Farah, Rana; Shea, Steven M.; Tryggestad, Erik; Hales, Russell; Lee, Junghoon

    2017-03-01

    Surrogate-based tumor motion estimation and tracing methods are commonly used in radiotherapy despite the lack of continuous real time 3D tumor and surrogate data. In this study, we propose a method to simultaneously track the tumor and external surrogates with dynamic MRI, which allows us to evaluate their reproducible correlation. Four MRIcompatible fiducials are placed on the patient's chest and upper abdomen, and multi-slice 2D cine MRIs are acquired to capture the lung and whole tumor, followed by two-slice 2D cine MRIs to simultaneously track the tumor and fiducials, all in sagittal orientation. A phase-binned 4D-MRI is first reconstructed from multi-slice MR images using body area as a respiratory surrogate and group-wise registration. The 4D-MRI provides 3D template volumes for different breathing phases. 3D tumor position is calculated by 3D-2D template matching in which 3D tumor templates in 4D-MRI reconstruction and the 2D cine MRIs from the two-slice tracking dataset are registered. 3D trajectories of the external surrogates are derived via matching a 3D geometrical model to the fiducial segmentations on the 2D cine MRIs. We tested our method on five lung cancer patients. Internal target volume from 4D-CT showed average sensitivity of 86.5% compared to the actual tumor motion for 5 min. 3D tumor motion correlated with the external surrogate signal, but showed a noticeable phase mismatch. The 3D tumor trajectory showed significant cycle-to-cycle variation, while the external surrogate was not sensitive enough to capture such variations. Additionally, there was significant phase mismatch between surrogate signals obtained from fiducials at different locations.

  14. Metastatic Pancreatic Neuroendocrine Tumor that Progressed to Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome with Growth Hormone-releasing Hormone (GHRH) Production

    PubMed Central

    Tadokoro, Rie; Sato, Shotaro; Otsuka, Fumiko; Ueno, Makoto; Ohkawa, Shinichi; Katakami, Hideki; Taniyama, Matsuo; Nagasaka, Shoichiro

    2016-01-01

    The patient was a 61-year-old woman who had a well-differentiated pancreatic neuroendocrine tumor (PNET) with lymph node metastasis. After 15 months of octreotide treatment, glucose control deteriorated and pigmentation of the tongue and moon face developed, leading to the diagnosis of ectopic adrenocorticotropic hormone (ACTH) syndrome. An abnormal secretion of growth hormone (GH) was identified, and the plasma growth hormone-releasing hormone (GHRH) level was elevated. A tumor biopsy specimen positively immunostained for ACTH and GHRH. Ectopic hormone secretion seems to have evolved along with the progression of the PNET. PMID:27746436

  15. Metastatic Pancreatic Neuroendocrine Tumor that Progressed to Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome with Growth Hormone-releasing Hormone (GHRH) Production.

    PubMed

    Tadokoro, Rie; Sato, Shotaro; Otsuka, Fumiko; Ueno, Makoto; Ohkawa, Shinichi; Katakami, Hideki; Taniyama, Matsuo; Nagasaka, Shoichiro

    The patient was a 61-year-old woman who had a well-differentiated pancreatic neuroendocrine tumor (PNET) with lymph node metastasis. After 15 months of octreotide treatment, glucose control deteriorated and pigmentation of the tongue and moon face developed, leading to the diagnosis of ectopic adrenocorticotropic hormone (ACTH) syndrome. An abnormal secretion of growth hormone (GH) was identified, and the plasma growth hormone-releasing hormone (GHRH) level was elevated. A tumor biopsy specimen positively immunostained for ACTH and GHRH. Ectopic hormone secretion seems to have evolved along with the progression of the PNET.

  16. Diclofenac Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer by Modulation of VEGF Levels and Arginase Activity

    PubMed Central

    Mayorek, Nina; Naftali-Shani, Nili; Grunewald, Myriam

    2010-01-01

    Background Diclofenac is one of the oldest anti-inflammatory drugs in use. In addition to its inhibition of cyclooxygenases (COX), diclofenac potently inhibits phospholipase A2 (PLA2), thus yielding a broad anti-inflammatory effect. Since inflammation is an important factor in the development of pancreatic tumors we explored the potential of diclofenac to inhibit tumor growth in mice inoculated with PANCO2 cells orthotopically. Methodology/Principal Findings We found that diclofenac treatment (30 mg/kg/bw for 11 days) of mice inoculated with PANC02 cells, reduced the tumor weight by 60%, correlating with increased apoptosis of tumor cells. Since this effect was not observed in vitro on cultured PANCO2 cells, we theorized that diclofenac beneficial treatment involved other mediators present in vivo. Indeed, diclofenac drastically decreased tumor vascularization by downregulating VEGF in the tumor and in abdominal cavity fluid. Furthermore, diclofenac directly inhibited vascular sprouting ex vivo. Surprisingly, in contrast to other COX-2 inhibitors, diclofenac increased arginase activity/arginase 1 protein content in tumor stroma cells, peritoneal macrophages and white blood cells by 2.4, 4.8 and 2 fold, respectively. We propose that the subsequent arginine depletion and decrease in NO levels, both in serum and peritoneal cavity, adds to tumor growth inhibition by malnourishment and poor vasculature development. Conclusion/Significance In conclusion, diclofenac shows pronounced antitumoral properties in pancreatic cancer model that can contribute to further treatment development. The ability of diclofenac to induce arginase activity in tumor stroma, peritoneal macrophages and white blood cells provides a tool to study a controversial issue of pro-and antitumoral effects of arginine depletion. PMID:20856806

  17. Pancreatic cancer

    MedlinePlus

    ... the cell the cancer develops in. Examples include: Adenocarcinoma, the most common type of pancreatic cancer Other ... idea of what to expect. Treatment Treatment for adenocarcinoma depends on the stage of the tumor. Surgery ...

  18. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids.

    PubMed

    Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B; Crawford, Howard C; Arrowsmith, Cheryl; Kalloger, Steve E; Renouf, Daniel J; Connor, Ashton A; Cleary, Sean; Schaeffer, David F; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K

    2015-11-01

    There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

  19. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell and patient-derived tumor organoids

    PubMed Central

    Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B.; Crawford, Howard C.; Arrowsmith, Cheryl; Kalloger, Steve E.; Renouf, Daniel J.; Connor, Ashton A; Cleary, Sean; Schaeffer, David F.; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K.

    2016-01-01

    There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies. PMID:26501191

  20. Efficacy of endoscopic ultrasonography-guided fine needle aspiration for pancreatic neuroendocrine tumor grading

    PubMed Central

    Sugimoto, Mitsuru; Takagi, Tadayuki; Hikichi, Takuto; Suzuki, Rei; Watanabe, Ko; Nakamura, Jun; Kikuchi, Hitomi; Konno, Naoki; Waragai, Yuichi; Asama, Hiroyuki; Takasumi, Mika; Watanabe, Hiroshi; Obara, Katsutoshi; Ohira, Hiromasa

    2015-01-01

    AIM: To evaluate the efficacy of endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) for grading pancreatic neuroendocrine tumors (PNETs). METHODS: A total of 22 patients were diagnosed with PNET by EUS-FNA between October 2001 and December 2013 at Fukushima Medical University Hospital. Among these cases, we targeted 10 PNET patients who were evaluated according to the World Health Organization (WHO) 2010 classification. Surgery was performed in eight patients, and chemotherapy was performed in two patients due to multiple liver metastases.Specimens obtained by EUS-FNA were first stained with hematoxylin and eosin and then stained with chromogranin, synaptophysin, CD56, and Ki-67. The specimens were graded by the Ki-67 index according to the WHO 2010 classification. Specimens obtained by surgery were graded by the Ki-67 index and mitotic count (WHO 2010 classification). For the eight specimens obtained by EUS-FNA, the Ki-67 index results were compared with those obtained by surgery. In the two cases treated with chemotherapy, the effects and prognoses were evaluated. RESULTS: The sampling rate for histological diagnosis by EUS-FNA was 100%. No adverse effects were observed. The concordance rate between specimens obtained by EUS-FNA and surgery was 87.5% (7/8). For the two cases treated with chemotherapy, case 1 received somatostatin analog therapy and transcatheter arterial infusion (TAI) targeting multiple liver metastases. Subsequent treatment consisted of everolimus. During chemotherapy, the primary tumor remained unconfirmed, although the multiple liver metastases diminished dramatically. Case 2 was classified as neuroendocrine carcinoma (NEC) according to the Ki-67 index of a specimen obtained by EUS-FNA; therefore, cisplatin and irinotecan therapy was started. However, severe adverse effects, including renal failure and diarrhea, were observed, and the therapy regimen was changed to cisplatin and etoposide. TAI targeting multiple liver

  1. Pancreatic Neuroendocrine Tumors With Involved Surgical Margins: Prognostic Factors and the Role of Adjuvant Radiotherapy

    SciTech Connect

    Arvold, Nils D.; Willett, Christopher G.; Fernandez-del Castillo, Carlos; Ryan, David P.; Ferrone, Cristina R.; Clark, Jeffrey W.; Blaszkowsky, Lawrence S.; Deshpande, Vikram; Niemierko, Andrzej; Allen, Jill N.; Kwak, Eunice L.; Wadlow, Raymond C.; Zhu, Andrew X.; Warshaw, Andrew L.; Hong, Theodore S.

    2012-07-01

    Purpose: Pancreatic neuroendocrine tumors (pNET) are rare neoplasms associated with poor outcomes without resection, and involved surgical margins are associated with a worse prognosis. The role of adjuvant radiotherapy (RT) in these patients has not been characterized. Methods and Materials: We retrospectively evaluated 46 consecutive patients with positive or close (<1 mm) margins after pNET resection, treated from 1983 to 2010, 16 of whom received adjuvant RT. Median RT dose was 50.4 Gy in 1.8-Gy fractions; half the patients received concurrent chemotherapy with 5-fluorouracil or capecitabine. No patients received adjuvant chemotherapy. Cox multivariate analysis (MVA) was used to analyze factors associated with overall survival (OS). Results: Median age at diagnosis was 56 years, and 52% of patients were female. Median tumor size was 38 mm, 57% of patients were node-positive, and 11% had a resected solitary liver metastasis. Patients who received RT were more likely to have larger tumors (median, 54 mm vs. 30 mm, respectively, p = 0.002) and node positivity (81% vs. 33%, respectively, p = 0.002) than those not receiving RT. Median follow-up was 39 months. Actuarial 5-year OS was 62% (95% confidence interval [CI], 41%-77%). In the group that did not receive RT, 3 patients (10%) experienced local recurrence (LR) and 5 patients (18%) developed new distant metastases, while in the RT group, 1 patient (6%) experienced LR and 5 patients (38%) developed distant metastases. Of all recurrences, 29% were LR. On MVA, male gender (adjusted hazard ratio [AHR] = 3.81; 95% CI, 1.21-11.92; p = 0.02) and increasing tumor size (AHR = 1.02; 95% CI, 1.01-1.04; p = 0.007) were associated with decreased OS. Conclusions: Long-term survival is common among patients with involved-margin pNET. Despite significantly worse pathologic features among patients receiving adjuvant RT, rates of LR between groups were similar, suggesting that RT might aid local control, and merits further

  2. SU-E-J-133: Evaluation of Inter- and Intra-Fractional Pancreas Tumor Residual Motions with Abdominal Compression

    SciTech Connect

    Li, Y; Shi, F; Tian, Z; Jia, X; Meyer, J; Jiang, S; Mao, W

    2014-06-01

    Purpose: Abdominal compression (AC) has been widely used to reduce pancreas motion due to respiration for pancreatic cancer patients undergoing stereotactic body radiotherapy (SBRT). However, the inter-fractional and intra-fractional patient motions may degrade the treatment. The purpose of this work is to study daily CBCT projections and 4DCT to evaluate the inter-fractional and intra-fractional pancreatic motions. Methods: As a standard of care at our institution, 4D CT scan was performed for treatment planning. At least two CBCT scans were performed for daily treatment. Retrospective studies were performed on patients with implanted internal fiducial markers or surgical clips. The initial motion pattern was obtained by extracting marker positions on every phase of 4D CT images. Daily motions were presented by marker positions on CBCT scan projection images. An adaptive threshold segmentation algorithm was used to extract maker positions. Both marker average positions and motion ranges were compared among three sets of scans, 4D CT, positioning CBCT, and conformal CBCT, for inter-fractional and intra-fractional motion variations. Results: Data from four pancreatic cancer patients were analyzed. These patients had three fiducial markers implanted. All patients were treated by an Elekta Synergy with single fraction SBRT. CBCT projections were acquired by XVI. Markers were successfully detected on most of the projection images. The inter-fractional changes were determined by 4D CT and the first CBCT while the intra-fractional changes were determined by multiple CBCT scans. It is found that the average motion range variations are within 2 mm, however, the average marker positions may drift by 6.5 mm. Conclusion: The patients respiratory motion variation for pancreas SBRT with AC was evaluated by detecting markers from CBCT projections and 4DCT, both the inter-fraction and intra-fraction motion range change is small but the drift of marker positions may be comparable

  3. Dose response of pancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy using 177Lu-DOTATATE.

    PubMed

    Ilan, Ezgi; Sandström, Mattias; Wassberg, Cecilia; Sundin, Anders; Garske-Román, Ulrike; Eriksson, Barbro; Granberg, Dan; Lubberink, Mark

    2015-02-01

    Peptide receptor radionuclide therapy (PRRT) is a promising treatment for patients with neuroendocrine tumors, giving rise to improved survival. Dosimetric calculations in relation to PRRT have been concentrated to normal organ dosimetry in order to limit side effects. However, the relation between the absorbed dose to the tumor and treatment response has so far not been established. Better knowledge in this respect may improve the understanding of treatment effects, allow for improved selection of those patients who are expected to benefit from PRRT, and avoid unnecessary treatments. The aim of the present work was to evaluate the dose-response relationship for pancreatic neuroendocrine tumors treated with PRRT using (177)Lu-DOTATATE. Tumor-absorbed dose calculations were performed for 24 lesions in 24 patients with metastasized pancreatic neuroendocrine tumors treated with repeated cycles of (177)Lu-DOTATATE at 8-wk intervals. The absorbed dose calculations relied on sequential SPECT/CT imaging at 24, 96, and 168 h after infusion of (177)Lu-DOTATATE. The unit density sphere model from OLINDA was used for absorbed dose calculations. The absorbed doses were corrected for partial-volume effect based on phantom measurements. On the basis of these results, only tumors larger than 2.2 cm in diameter at any time during the treatment were included for analysis. To further decrease the effect of partial-volume effect, a subgroup of tumors (>4.0 cm) was analyzed separately. Tumor response was evaluated by CT using Response Evaluation Criteria In Solid Tumors. Tumor-absorbed doses until best response ranged approximately from 10 to 340 Gy. A 2-parameter sigmoid fit was fitted to the data, and a significant correlation between the absorbed dose and tumor reduction was found, with a Pearson correlation coefficient (R(2)) of 0.64 for tumors larger than 2.2 cm and 0.91 for the subgroup of tumors larger than 4.0 cm. The largest tumor reduction was 57% after a total absorbed dose

  4. Histopathologic tumor response after induction chemotherapy and stereotactic body radiation therapy for borderline resectable pancreatic cancer

    PubMed Central

    Chuong, Michael D.; Frakes, Jessica M.; Figura, Nicholas; Hoffe, Sarah E.; Shridhar, Ravi; Mellon, Eric A.; Hodul, Pamela J.; Malafa, Mokenge P.; Springett, Gregory M.

    2016-01-01

    Background While clinical outcomes following induction chemotherapy and stereotactic body radiation therapy (SBRT) have been reported for borderline resectable pancreatic cancer (BRPC) patients, pathologic response has not previously been described. Methods This single-institution retrospective review evaluated BRPC patients who completed induction gemcitabine-based chemotherapy followed by SBRT and surgical resection. Each surgical specimen was assigned two tumor regression grades (TRG), one using the College of American Pathologists (CAP) criteria and one using the MD Anderson Cancer Center (MDACC) criteria. Overall survival (OS) and progression free survival (PFS) were correlated to TRG score. Results We evaluated 36 patients with a median follow-up of 13.8 months (range, 6.1-24.8 months). The most common induction chemotherapy regimen (82%) was GTX (gemcitabine, docetaxel, capecitabine). A median SBRT dose of 35 Gy (range, 30-40 Gy) in 5 fractions was delivered to the region of vascular involvement. The margin-negative resection rate was 97.2%. Improved response according to MDACC grade trended towards superior PFS (P=061), but not OS. Any neoadjuvant treatment effect according to MDACC scoring (IIa-IV vs. I) was associated with improved OS and PFS (both P=0.019). We found no relationship between CAP score and OS or PFS. Conclusions These data suggest that the increased pathologic response after induction chemotherapy and SBRT is correlated with improved survival for BRPC patients. PMID:27034789

  5. Epidrug-induced upregulation of functional somatostatin type 2 receptors in human pancreatic neuroendocrine tumor cells.

    PubMed

    Veenstra, Marije J; van Koetsveld, Peter M; Dogan, Fadime; Farrell, William E; Feelders, Richard A; Lamberts, Steven W J; de Herder, Wouter W; Vitale, Giovanni; Hofland, Leo J

    2016-05-19

    Somatostatin receptors are a pivotal target for treatment of pancreatic neuroendocrine tumors (pNET), either with somatostatin analogues (SSA) or radiolabeled SSA. The highest affinity target for the most commonly used SSA is the somatostatin receptor type 2 (sst2). An important factor that may complicate treatment efficacy, is the variable number of receptors expressed on pNETs. Gene expression is subject to complex regulation, in which epigenetics has a central role. In this study we explored the possible role of epigenetic modifications in the variations in sst2 expression levels in two human pNET cell lines, BON-1 and QGP-1. We found upregulation of sst2 mRNA after treatment with the epidrugs 5-aza-2'-deoxycytidine (5-aza-dC) and valproic acid (VPA), an increased uptake of radiolabeled octreotide, as well as increased sensitivity to the SSA octreotide in functional cAMP inhibition. At epigenetic level we observed low methylation levels of the sst2 gene promoter region irrespective of expression. Activating histone mark H3K9Ac can be regulated with epidrug treatment, with an angle of effect corresponding to the effect on mRNA expression. Repressive histone mark H3K27me3 is not regulated by either 5-aza-dC or VPA. We conclude that epidrug treatment, in particular with combined 5-aza-dC and VPA treatment, might hold promise for improving and adding to current SSA treatment strategies of patients with pNETs.

  6. Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies

    PubMed Central

    Jensen, Robert T.; Berna, Marc J.; Bingham, David B; Norton, Jeffrey A.

    2008-01-01

    Pancreatic endocrine tumors (PETs) can occur in as part of four inherited disorders including: Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1(NF-1) [von Recklinghausen’s disease] and the tuberous sclerosis complex (TSC). The relative frequency with which patients with these disorders develop PETs is MEN1>VHL>NF-1>TSC. Over the last few years there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization, medical and surgical treatment of the PETs in these patients. The study of the PETs in these disorders has not only provided insights into the possible pathogenesis of sporadic PETs, but have also presented a number of unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore the study of PETs in these uncommon disorders has provided valuable insights that in many cases are applicable to the general group of patients with sporadic PETs. In this article these areas are briefly reviewed as well as the current state of knowledge of the PETs in these disorders and the controversies that exist in their management are briefly summarized and discussed. PMID:18798544

  7. Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer

    PubMed Central

    Takai, Erina; Totoki, Yasushi; Nakamura, Hiromi; Morizane, Chigusa; Nara, Satoshi; Hama, Natsuko; Suzuki, Masami; Furukawa, Eisaku; Kato, Mamoru; Hayashi, Hideyuki; Kohno, Takashi; Ueno, Hideki; Shimada, Kazuaki; Okusaka, Takuji; Nakagama, Hitoshi; Shibata, Tatsuhiro; Yachida, Shinichi

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. The genomic landscape of the PDAC genome features four frequently mutated genes (KRAS, CDKN2A, TP53, and SMAD4) and dozens of candidate driver genes altered at low frequency, including potential clinical targets. Circulating cell-free DNA (cfDNA) is a promising resource to detect and monitor molecular characteristics of tumors. In the present study, we determined the mutational status of KRAS in plasma cfDNA using multiplex picoliter-droplet digital PCR in 259 patients with PDAC. We constructed a novel modified SureSelect-KAPA-Illumina platform and an original panel of 60 genes. We then performed targeted deep sequencing of cfDNA and matched germline DNA samples in 48 patients who had ≥1% mutant allele frequencies of KRAS in plasma cfDNA. Importantly, potentially targetable somatic mutations were identified in 14 of 48 patients (29.2%) examined by targeted deep sequencing of cfDNA. We also analyzed somatic copy number alterations based on the targeted sequencing data using our in-house algorithm, and potentially targetable amplifications were detected. Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients. PMID:26669280

  8. Liquid biopsy in patients with pancreatic cancer: Circulating tumor cells and cell-free nucleic acids.

    PubMed

    Imamura, Taisuke; Komatsu, Shuhei; Ichikawa, Daisuke; Kawaguchi, Tsutomu; Miyamae, Mahito; Okajima, Wataru; Ohashi, Takuma; Arita, Tomohiro; Konishi, Hirotaka; Shiozaki, Atsushi; Morimura, Ryo; Ikoma, Hisashi; Okamoto, Kazuma; Otsuji, Eigo

    2016-07-07

    Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer (PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis. In the blood of patients with cancer, circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs), such as DNA, mRNA, and noncoding RNA have been recognized. In the recent years, their presence in the blood has encouraged researchers to investigate their potential use as novel blood biomarkers, and numerous studies have demonstrated their potential clinical utility as a biomarker for certain types of cancer. This concept, called "liquid biopsy" has been focused on as a less invasive, alternative approach to cancer tissue biopsy for obtaining genetic and epigenetic aberrations that contribute to oncogenesis and cancer progression. In this article, we review the available literature on CTCs and cfNAs in patients with cancer, particularly focusing on PCa, and discuss future perspectives in this field.

  9. Perfusion CT Changes in Liver Metastases from Pancreatic Neuroendocrine Tumors During Everolimus Treatment.

    PubMed

    D'Onofrio, Mirko; Cingarlini, Sara; Ortolani, Silvia; Crosara, Stefano; DE Robertis, Riccardo; Vallerio, Paola; Grego, Elisabetta; Ciaravino, Valentina; Ruzzenente, Andrea; Landoni, Luca; Scarpa, Aldo; Bassi, Claudio; Tortora, Giampaolo

    2017-03-01

    To evaluate modifications of perfusional parameters assessed by perfusion computed tomography (P-CT) of liver metastases (LM) from pancreatic neuroendocrine tumors (PanNETs) during everolimus treatment. All patients with LMs from G1-2 PanNETs undergoing everolimus treatment between January 2013 and January 2015 were prospectively evaluated with P-CT at baseline, and after 2 and 4 months of therapy. Size, perfusion, blood volume (BV), peak enhancement intensity (PEI) and time to peak for each lesion were calculated. A total of 33 LMs in nine patients with G1-2 PanNETs were prospectively evaluated: 23/33 (69.7%) were responders, 10/33 (30.3%) were non-responders. Among perfusional parameters, only numerical peak enhancement intensity values significantly differed between the two groups at baseline (p=0.043). BV increase was the most significant perfusional modification identifying responding lesions, even at an early stage of treatment, with a high positive predictive value (89.47%). P-CT seems to be useful for prediction of response to everolimus of LMs from PanNETs. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  10. Liquid biopsy in patients with pancreatic cancer: Circulating tumor cells and cell-free nucleic acids

    PubMed Central

    Imamura, Taisuke; Komatsu, Shuhei; Ichikawa, Daisuke; Kawaguchi, Tsutomu; Miyamae, Mahito; Okajima, Wataru; Ohashi, Takuma; Arita, Tomohiro; Konishi, Hirotaka; Shiozaki, Atsushi; Morimura, Ryo; Ikoma, Hisashi; Okamoto, Kazuma; Otsuji, Eigo

    2016-01-01

    Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer (PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis. In the blood of patients with cancer, circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs), such as DNA, mRNA, and noncoding RNA have been recognized. In the recent years, their presence in the blood has encouraged researchers to investigate their potential use as novel blood biomarkers, and numerous studies have demonstrated their potential clinical utility as a biomarker for certain types of cancer. This concept, called “liquid biopsy” has been focused on as a less invasive, alternative approach to cancer tissue biopsy for obtaining genetic and epigenetic aberrations that contribute to oncogenesis and cancer progression. In this article, we review the available literature on CTCs and cfNAs in patients with cancer, particularly focusing on PCa, and discuss future perspectives in this field. PMID:27433079

  11. Histopathologic tumor response after induction chemotherapy and stereotactic body radiation therapy for borderline resectable pancreatic cancer.

    PubMed

    Chuong, Michael D; Frakes, Jessica M; Figura, Nicholas; Hoffe, Sarah E; Shridhar, Ravi; Mellon, Eric A; Hodul, Pamela J; Malafa, Mokenge P; Springett, Gregory M; Centeno, Barbara A

    2016-04-01

    While clinical outcomes following induction chemotherapy and stereotactic body radiation therapy (SBRT) have been reported for borderline resectable pancreatic cancer (BRPC) patients, pathologic response has not previously been described. This single-institution retrospective review evaluated BRPC patients who completed induction gemcitabine-based chemotherapy followed by SBRT and surgical resection. Each surgical specimen was assigned two tumor regression grades (TRG), one using the College of American Pathologists (CAP) criteria and one using the MD Anderson Cancer Center (MDACC) criteria. Overall survival (OS) and progression free survival (PFS) were correlated to TRG score. We evaluated 36 patients with a median follow-up of 13.8 months (range, 6.1-24.8 months). The most common induction chemotherapy regimen (82%) was GTX (gemcitabine, docetaxel, capecitabine). A median SBRT dose of 35 Gy (range, 30-40 Gy) in 5 fractions was delivered to the region of vascular involvement. The margin-negative resection rate was 97.2%. Improved response according to MDACC grade trended towards superior PFS (P=061), but not OS. Any neoadjuvant treatment effect according to MDACC scoring (IIa-IV vs. I) was associated with improved OS and PFS (both P=0.019). We found no relationship between CAP score and OS or PFS. These data suggest that the increased pathologic response after induction chemotherapy and SBRT is correlated with improved survival for BRPC patients.

  12. Four-dimensional multislice computed tomography for determination of respiratory lung tumor motion in conformal radiotherapy

    SciTech Connect

    Leter, Edward M. . E-mail: emleter@hotmail.com; Cademartiri, Filippo; Levendag, Peter C.; Flohr, Thomas; Stam, Henk; Nowak, Peter J.

    2005-07-01

    Purpose: We used four-dimensional multislice spiral computed tomography (MSCT) to determine respiratory lung-tumor motion and compared this strategy to common clinical practice in conformal radiotherapy treatment-planning imaging. Methods and Materials: The entire lung volume of 10 consecutive patients with 14 lung metastases were scanned by a 16-slice MSCT. During the scans, patients were instructed to breathe through a spirometer that was connected to a laptop computer. For each patient, 10 stacks of 1.5-mm slices, equally distributed throughout the respiratory cycle, were reconstructed from the acquired MSCT data. The lung tumors were manually contoured in each data set. For each patient, the tumor-volume contours of all data sets were copied to 1 data set, which allowed determination of the volume that encompassed all 10 lung-tumor positions (i.e., the tumor-traversed volume [TTV]) during the respiratory cycle. The TTV was compared with the 10 tumor volumes contoured for each patient, to which an empiric respiratory-motion margin was added. The latter target volumes were designated internal-motion included tumor volume (IMITV). Results: The TTV measurements were significantly smaller than the reference IMITV measurements (5.2 {+-} 10.2 cm{sup 3} and 10.1 {+-} 13.7 cm{sup 3}, respectively). All 10 IMITVs for 2 of the 4 tumors in 1 subject completely encompassed the TTV. All 10 IMITVs for 3 tumors in 2 patients did not show overlap with up to 35% of the corresponding TTV. The 10 IMITVs for the remaining tumors either completely encompassed the corresponding TTV or did not show overlap with up to 26% of the corresponding TTV. Conclusions: We found that individualized determination of respiratory lung-tumor motion by four-dimensional respiratory-gated MSCT represents a better and simple strategy to incorporate periodic physiologic motion compared with a generalized approach. The former strategy can, therefore, improve common and state-of-the-art clinical practice

  13. Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1.

    PubMed

    Vandamme, Timon; Peeters, Marc; Dogan, Fadime; Pauwels, Patrick; Van Assche, Elvire; Beyens, Matthias; Mortier, Geert; Vandeweyer, Geert; de Herder, Wouter; Van Camp, Guy; Hofland, Leo J; Op de Beeck, Ken

    2015-04-01

    The human BON-1 and QGP-1 cell lines are two frequently used models in pancreatic neuroendocrine tumor (PNET) research. Data on the whole-exome genetic constitution of these cell lines is largely lacking. This study presents, to our knowledge, the first whole-exome profile of the BON-1 and QGP-1 cell lines. Cell line identity was confirmed by short tandem repeat profiling. Using GTG-banding and a CytoSNP-12v2 Beadchip array, cell line ploidy and chromosomal alterations were determined in BON-1 and QGP-1. The exomes of both cell lines were sequenced on Ilumina's HiSeq next-generation sequencing (NGS) platform. Single-nucleotide variants (SNVs) and insertions and deletions (indels) were detected using the Genome Analysis ToolKit. SNVs were validated by Sanger sequencing. Ploidy of BON-1 and QGP-1 was 3 and 4 respectively, with long stretches of loss of heterozygosity across multiple chromosomes, which is associated with aggressive tumor behavior. In BON-1, 57 frameshift indels and 1725 possible protein-altering SNVs were identified in the NGS data. In the QGP-1 cell line, 56 frameshift indels and 1095 SNVs were identified. ATRX, a PNET-associated gene, was mutated in both cell lines, while mutation of TSC2 was detected in BON-1. A mutation in NRAS was detected in BON-1, while KRAS was mutated in QGP-1, implicating aberrations in the RAS pathway in both cell lines. Homozygous mutations in TP53 with possible loss of function were identified in both cell lines. Various MUC genes, implicated in cell signaling, lubrication and chemical barriers, which are frequently expressed in PNET tissue samples, showed homozygous protein-altering SNVs in the BON-1 and QGP-1 cell lines.

  14. Nonfunctioning, small, incidental pancreatic neuroendocrine tumors: Results of a nonoperative approach cohort.

    PubMed

    Uribe Galeano, Catalina; Fabregat Prous, Joan; Busquets Barenys, Juli; Pelaez Serra, Nuria; Secanella Medayo, Lluís; Ramos Rubio, Emilio; Ruiz Osuna, Sandra; Villabona Artero, Carlos

    2017-02-01

    The availability of new imaging techniques has conditioned an increase in the incidental diagnosis of small nonfunctioning pancreatic neuroendocrine tumors (PNET-NF). The best treatment is controversial, some authors advise a conservative approach in selected cases. Our aim is to analyze the evolution of incidental, small size PNET-NF, treated with clinical follow-up without surgery. We performed a retrospective analysis of a prospective database of patients diagnosed incidentally with PNET-NF since November 2007 to September 2015. We include those with PNET-NF ≤2cm and asymptomatic. The diagnosis was performed using imaging tests indicating endoscopic ultrasound-guided fine-needle aspiration in case of doubts in the diagnosis. The follow-up was performed at our center, registering clinical and/or radiological changes. We included 24 patients with a median age of 70 years, and a similar distribution in terms of sex. The diagnosis was made through computed tomography multidetector or magnetic resonance imaging and octreotide scan. The tumors were located mainly in the head and neck (46%), with a mean size of 11,5±3,55mm at diagnosis (5-19mm). In 2 cases endoscopic ultrasound fine needle aspiration was used (8%), confirming the diagnosis of low-grade PNET with Ki67<5%. The median follow-up was 39 months (7-100). In 19 patients (79%) they remained the same size, 21% (5) increased its size with a mean of 2,6±2mm (1-6). No cases had progression of disease. In selected patients, non-surgical management of PNET-NF is an option to consider, when they are asymptomatic and ≤2cm. Larger studies with more patients and more time of follow-up are needed to validate this non-operative approach. Copyright © 2016 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

  15. Unique metabolic features of pancreatic cancer stroma: relevance to the tumor compartment, prognosis, and invasive potential

    PubMed Central

    Knudsen, Erik S.; Balaji, Uthra; Freinkman, Elizaveta; McCue, Peter; Witkiewicz, Agnieszka K.

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The aggressiveness and therapeutic recalcitrance of this malignancy has been attributed to multiple factors including the influence of an active desmoplastic stroma. How the stromal microenvironment of PDAC contributes to the fatal nature of this disease is not well defined. In the analysis of clinical specimens, we observed diverse expression of the hypoxic marker carbonic anhydrase IX and the lactate transporter MCT4 in the stromal compartment. These stromal features were associated with the epithelial to mesenchymal phenotype in PDAC tumor cells, and with shorter patient survival. Cultured cancer-associated fibroblasts (CAFs) derived from primary PDAC exhibited a high basal level of hypoxia inducible factor 1a (HIF1α) that was both required and sufficient to modulate the expression of MCT4. This event was associated with increased transcription and protein synthesis of HIF1α in CAFs relative to PDAC cell lines, while surprisingly the protein turnover rate was equivalent. CAFs utilized glucose predominantly for glycolytic intermediates, whereas glutamine was the preferred metabolite for the TCA cycle. Unlike PDAC cell lines, CAFs were resistant to glucose withdrawal but sensitive to glutamine depletion. Consistent with the lack of reliance on glucose, CAFs could survive the acute depletion of MCT4. In co-culture and xenograft studies CAFs stimulated the invasive potential and metastatic spread of PDAC cell lines through a mechanism dependent on HIF1α and MCT4. Together, these data indicate that stromal metabolic features influence PDAC tumor cells to promote invasiveness and metastatic potential and associate with poor outcome in patients with PDAC. PMID:27623078

  16. Circulating Tumor Cell Phenotype Predicts Recurrence and Survival in Pancreatic Adenocarcinoma

    PubMed Central

    Poruk, Katherine E.; Valero, Vicente; Saunders, Tyler; Blackford, Amanda L.; Griffin, James F.; Poling, Justin; Hruban, Ralph H.; Anders, Robert A.; Herman, Joseph; Zheng, Lei; Rasheed, Zeshaan A.; Laheru, Daniel A.; Ahuja, Nita; Weiss, Matthew J.; Cameron, John L.; Goggins, Michael; Iacobuzio-Donahue, Christine A.; Wood, Laura D.; Wolfgang, Christopher L.

    2016-01-01

    Objective We assessed circulating tumor cells (CTCs) with epithelial and mesenchymal phenotypes as a potential prognostic biomarker for patients with pancreatic adenocarcinoma (PDAC). Background PDAC is the fourth leading cause of cancer death in the United States. There is an urgent need to develop biomarkers that predict patient prognosis and allow for better treatment stratification. Methods Peripheral and portal blood samples were obtained from 50 patients with PDAC before surgical resection and filtered using the Isolation by Size of Epithelial Tumor cells method. CTCs were identified by immunofluorescence using commercially available antibodies to cytokeratin, vimentin, and CD45. Results Thirty-nine patients (78%) had epithelial CTCs that expressed cytokeratin but not CD45. Twenty-six (67%) of the 39 patients had CTCs which also expressed vimentin, a mesenchymal marker. No patients had cytokeratin-negative and vimentin-positive CTCs. The presence of cytokeratin-positive CTCs (P < 0.01), but not mesenchymal-like CTCs (P = 0.39), was associated with poorer survival. The presence of cytokeratin-positive CTCs remained a significant independent predictor of survival by multi-variable analysis after accounting for other prognostic factors (P < 0.01). The detection of CTCs expressing both vimentin and cytokeratin was predictive of recurrence (P = 0.01). Among patients with cancer recurrence, those with vimentin-positive and cytokeratin-expressing CTCs had decreased median time to recurrence compared with patients without CTCs (P = 0.02). Conclusions CTCs are an exciting potential strategy for understanding the biology of metastases, and provide prognostic utility for PDAC patients. CTCs exist as heterogeneous populations, and assessment should include phenotypic identification tailored to characterize cells based on epithelial and mesenchymal markers. PMID:26756760

  17. Pancreatic Exocrine Insufficiency in Pancreatic Cancer.

    PubMed

    Vujasinovic, Miroslav; Valente, Roberto; Del Chiaro, Marco; Permert, Johan; Löhr, J-Matthias

    2017-02-23

    Abstract: Cancer patients experience weight loss for a variety of reasons, commencing with the tumor's metabolism (Warburg effect) and proceeding via cachexia to loss of appetite. In pancreatic cancer, several other factors are involved, including a loss of appetite with a particular aversion to meat and the incapacity of the pancreatic gland to function normally when a tumor is present in the pancreatic head. Pancreatic exocrine insufficiency is characterized by a deficiency of the enzymes secreted from the pancreas due to the obstructive tumor, resulting in maldigestion. This, in turn, contributes to malnutrition, specifically a lack of fat-soluble vitamins, antioxidants, and other micronutrients. Patients with pancreatic cancer and pancreatic exocrine insufficiency have, overall, an extremely poor prognosis with regard to surgical outcome and overall survival. Therefore, it is crucial to be aware of the mechanisms involved in the disease, to be able to diagnose pancreatic exocrine insufficiency early on, and to treat malnutrition appropriately, for example, with pancreatic enzymes.

  18. Dosimetric variances anticipated from breathing- induced tumor motion during tomotherapy treatment delivery.

    PubMed

    Chaudhari, S R; Goddu, S M; Rangaraj, D; Pechenaya, O L; Lu, W; Kintzel, E; Malinowski, K; Parikh, P J; Bradley, J D; Low, D A

    2009-04-21

    In their classic paper, Yu et al (1998 Phys. Med. Biol. 43 91) investigated the interplay between tumor motion caused by breathing and dynamically collimated, intensity-modulated radiation delivery. The paper's analytic model assumed an idealized, sinusoidal pattern of motion. In this work, we investigate the effect of tumor motion based on patients' breathing patterns for typical tomotherapy treatments with field widths of 1.0 and 2.5 cm. The measured breathing patterns of 52 lung- and upper-abdominal-cancer patients were used to model a one-dimensional motion. A convolution of the measured beam-dose profiles with the motion model was used to compute the dose-distribution errors, and the positive and negative dose errors were recorded for each simulation. The dose errors increased with increasing motion magnitude, until the motion was similar in magnitude to the field width. For the 1.0 cm and 2.5 cm field widths, the maximum dose-error magnitude exceeded 10% in some simulations, even with breathing-motion magnitudes as small as 5 mm and 10 mm, respectively. Dose errors also increased slightly with increasing couch speed. We propose that the errors were due to subtle drifts in the amplitude and frequency of breathing motion, as well as changes in baseline (exhalation) position, causing both over- and under-dosing of the target. The results of this study highlight potential breathing-motion-induced dose delivery errors in tomotherapy. However, for conventionally fractionated treatments, the dose delivery errors may not be co-located and may average out over many fractions, although this may not be true for hypofractionated treatments.

  19. Dosimetric variances anticipated from breathing- induced tumor motion during tomotherapy treatment delivery

    NASA Astrophysics Data System (ADS)

    Chaudhari, S. R.; Goddu, S. M.; Rangaraj, D.; Pechenaya, O. L.; Lu, W.; Kintzel, E.; Malinowski, K.; Parikh, P. J.; Bradley, J. D.; Low, D. A.

    2009-04-01

    In their classic paper, Yu et al (1998 Phys. Med. Biol. 43 91) investigated the interplay between tumor motion caused by breathing and dynamically collimated, intensity-modulated radiation delivery. The paper's analytic model assumed an idealized, sinusoidal pattern of motion. In this work, we investigate the effect of tumor motion based on patients' breathing patterns for typical tomotherapy treatments with field widths of 1.0 and 2.5 cm. The measured breathing patterns of 52 lung- and upper-abdominal-cancer patients were used to model a one-dimensional motion. A convolution of the measured beam-dose profiles with the motion model was used to compute the dose-distribution errors, and the positive and negative dose errors were recorded for each simulation. The dose errors increased with increasing motion magnitude, until the motion was similar in magnitude to the field width. For the 1.0 cm and 2.5 cm field widths, the maximum dose-error magnitude exceeded 10% in some simulations, even with breathing-motion magnitudes as small as 5 mm and 10 mm, respectively. Dose errors also increased slightly with increasing couch speed. We propose that the errors were due to subtle drifts in the amplitude and frequency of breathing motion, as well as changes in baseline (exhalation) position, causing both over- and under-dosing of the target. The results of this study highlight potential breathing-motion-induced dose delivery errors in tomotherapy. However, for conventionally fractionated treatments, the dose delivery errors may not be co-located and may average out over many fractions, although this may not be true for hypofractionated treatments.

  20. MiR-145 functions as a tumor suppressor via regulating angiopoietin-2 in pancreatic cancer cells.

    PubMed

    Wang, Hao; Hang, Cheng; Ou, Xi-Long; Nie, Jin-Shan; Ding, Yi-Tao; Xue, Shi-Gui; Gao, Hua; Zhu, Jian-Xin

    2016-01-01

    Pancreatic cancer is currently one of the leading causes of cancer deaths without any effective therapies. Mir-145 has been found to be tumor-suppressive in various types of cancers. The aim of this study is to investigate the role of miR-145 in pancreatic cancer cells and explore its underlying mechanism. Quantitative real time PCR was used to determine the expression level of miR-145 and angiopoietin-2 (Ang-2) mNRA, and the expression level of Ang-2 protein was measured by western blotting. The anti-cancer activities of miR-145 were tested both in in vitro by using cell invasion and colony formation assay and in vivo by using xenograft assay. The direct action of miR-145 on Ang-2 was predicted by TargetScan and confirmed by luciferase report assay. The vascularization of xenografts were performed by immunohistochemical analysis. The expression level of miR-145 was significantly lower and the expression levels of Ang-2 mRNA and protein was significantly higher in the more aggressive pancreatic cancer cells (MiaPaCa-2 and Panc-1) when compared to that in BxPC3 cells. Overexpression of miR-145 in the BxPC3, MiaPaCa-2 and Panc-1 cells suppressed the cell invasion and colony formation ability, and the expression level of Ang-2 protein in MiaPaCa-2 and Panc-1 cells was also suppressed after pre-miR-145 transfection. Intratumoral delivery of miR-145 inhibited the growth of pancreatic cancer xenografts and angiogenesis in vivo, and also suppressed the expression level of angiopoietin-2 protein. Luciferase report assay showed that Ang-2 is a direct target of miR-145, and down-regulation of angiopoietin-2 by treatment with Ang-2 siRNA in the BxPC3, MiaPaCa-2 and Panc-1 cells suppressed cell invasion and colony formation ability. The reverse transcription PCR results also showed that Tie1 and Tie2 were expressed in BxPC3, MiaPaCa-2 and Panc-1 cells. MiR-145 functions as a tumor suppressor in pancreatic cancer cells by targeting Ang-2 for translation repression and thus

  1. Pancreatic Ductal Adenocarcinoma (PDA) mice lacking Mucin 1 have a profound defect in tumor growth and metastasis

    PubMed Central

    Besmer, Dahlia M.; Curry, Jennifer M.; Roy, Lopamudra D.; Tinder, Teresa L.; Sahraei, Mahnaz; Schettini, Jorge; Hwang, Sun-Il; Lee, Yong Y.; Gendler, Sandra J.; Mukherjee, Pinku

    2011-01-01

    MUC1 is over expressed and aberrantly glycosolated in >60% of pancreatic ductal adenocarcinomas. The functional role of MUC1 in pancreatic cancer has yet to be fully elucidated due to a dearth of appropriate models. In the present study, we have generated mouse models that spontaneously develop pancreatic ductal adenocarcinoma (KC), which are either Muc1-null (KCKO) or express human MUC1 (KCM). We show that KCKO mice have significantly slower tumor progression and rates of secondary metastasis, compared to both KC and KCM. Cell lines derived from KCKO tumors have significantly lower tumorigenic capacity compared to cells from KCM tumors. Therefore, mice with KCKO tumors had a significant survival benefit compared to mice with KCM tumors. In vitro, KCKO cells have reduced proliferation and invasion and failed to respond to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), or matrix metalloproteinase-9 (MMP9). Further, significantly fewer KCKO cells entered the G2M phase of the cell cycle compared to the KCM cells. Proteomics and western blotting analysis revealed a complete loss of cdc-25c expression, phosphorylation of MAPK, as well as a significant decrease in Nestin and Tubulin α-2 chain expression in KCKO cells. Treatment with a MEK1/2 inhibitor, U0126, abrogated the enhanced proliferation of the KCM cells but had minimal effect on KCKO cells, suggesting that MUC1 is necessary for MAPK activity and oncogenic signaling. This is the first study to utilize a Muc1-null PDA mouse in order to fully elucidate the oncogenic role of MUC1, both in vivo and in vitro. PMID:21558393

  2. Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in pancreatic ductal adenocarcinoma.

    PubMed

    Zhang, Lingfu; Guo, Limei; Tao, Ming; Fu, Wei; Xiu, Dianrong

    2016-04-01

    To investigate the frequency of parasympathetic neurogenesis and determine its association with tumor budding and prognosis in pancreatic ductal adenocarcinoma (PDAC). Parasympathetic neurogenesis was defined as the distribution of abnormal parasympathetic nerves in the stroma tissue. Staining of vesicular acetylcholine transporter (VAChT), as a marker for parasympathetic neurogenesis, was performed on a representative specimen of the tumor for 59 PDAC patients with available clinical, pathologic, and follow-up information. Three specimens containing normal pancreatic tissues were stained in parallel. The number of parasympathetic nerve fibers was counted in five high-power microscopic fields (5×0.785 mm(2)). Cut-off values were calculated by receiver operating characteristic curve analysis. VAChT-positive parasympathetic nerve fibers were not seen in the stroma of 3 cases of normal pancreatic tissues. In 59 PDAC cases, the range of parasympathetic neurogenesis was 4-38 fibers/(5×0.785) mm(2), with a median of 18 fibers/(5×0.785) mm(2). Patients with parasympathetic neurogenesis >15 fibers/(5×0.785) mm(2) were defined as the high-density group (39 patients, 66.1%), and those with parasympathetic neurogenesis 15 fibers/(5×0.785) mm(2) as the low-density group (20 patients, 33.9%). The high-density group had a higher occurrence of tumor budding (P=0.001) and a higher rate of early recurrence (P=0.035). Parasympathetic neurogenesis appeared to be an independent adverse prognostic factor [hazard ratio (HR)=2.45, 95% confidence interval (95% CI): 1.25-4.81, P=0.009], in addition to American Joint Committee on Cancer (AJCC) stage (P=0.010) and tumor budding (P=0.009). Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in PDAC.

  3. Effect of antidepressants on body weight, ethology and tumor growth of human pancreatic carcinoma xenografts in nude mice.

    PubMed

    Jia, Lin; Shang, Yuan-Yuan; Li, Yu-Yuan

    2008-07-21

    To investigate the effects of mirtazapine and fluoxetine, representatives of the noradrenergic and specific serotonergic antidepressant (NaSSA) and selective serotonin reuptake inhibitor (SSRI) antidepressant respectively, on body weight, ingestive behavior, locomotor activity and tumor growth of human pancreatic carcinoma xenografts in nude mice. A subcutaneous xenograft model of human pancreatic cancer cell line SW1990 was established in nude mice. The tumor-bearing mice were randomly divided into mirtazapine group (10 mg/kg per day), fluoxetine group (10 mg/kg per day) and control group (an equivalent normal saline solution) (7 mice in each group). Doses of all drugs were administered orally, once a day for 42 d. Tumor volume and body weight were measured biweekly. Food intake was recorded once a week. Locomotor activity was detected weekly using an open field test (OFT). Compared to the fluoxetine, mirtazapine significantly increased food intake from d 14 to 42 and attenuated the rate of weight loss from d 28 to 42 (t = 4.38, P < 0.05). Compared to the control group, food intake was significantly suppressed from d 21 to 42 and weight loss was promoted from d 35 to 42 in the fluoxetine group (t = 2.52, P < 0.05). There was a significant difference in body weight of the mice after removal of tumors among the three groups. The body weight of mice was the heaviest (13.66 +/- 1.55 g) in the mirtazapine group and the lightest (11.39 +/- 1.45 g) in the fluoxetine group (F( (2,12) ) = 11.43, P < 0.01). The behavioral test on d 7 showed that the horizontal and vertical activities were significantly increased in the mirtazapine group compared with the fluoxetine and control groups (F( (2,18) ) = 10.89, P < 0.01). These effects disappeared in the mirtazapine and fluoxetine groups during 2-6 wk. The grooming activity was higher in the mirtazapine group than in the fluoxetine group (10.1 +/- 2.1 vs 7.1 +/- 1.9 ) (t = 2.40, P < 0.05) in the second week. There was no

  4. Nerve growth factor regulates CD133 function to promote tumor cell migration and invasion via activating ERK1/2 signaling in pancreatic cancer.

    PubMed

    Xin, Beibei; He, Xiaodan; Wang, Juan; Cai, Jun; Wei, Wei; Zhang, Ti; Shen, Xiaohong

    Perineural invasion (PNI) is extremely high frequency among the various metastatic routes in pancreatic cancer. Nerve growth factor, secreted by astroglial cells, exerts effects on tumor invasion in some cancer cells, but its function on migration and invasion in pancreatic cancer is still unclear. In the present study, we determined the effects of NGF on modulating tumor cell metastatic potential and invasion activity and explored its mechanisms in pancreatic cancer. NGF and CD133 expression were detected in tumor tissues using immunohistochemical analysis and Western blotting analysis. The effects of NGF on the regulation of CD133 expression and the promotion of cancer migration and invasion were investigated using wound healing and matrigel transwell assay. A related mechanism that NGF regulates CD133's function via activating ERK1/2 signaling also was observed. NGF/CD133 is overexpressed in human pancreatic cancer and promotes the migration and invasion of human pancreatic cancer cells through the activation of the ERK/CD133 signaling cascade. NGF/ERK signaling modulates the cancer cell EMT process, migration and invasion through the regulation of CD133 expression and its subcellular localization. NGF/CD133 signaling initiated the migration and invasion of pancreatic cancer cells. NGF/CD133 might be an effective and potent therapeutic target for pancreatic cancer metastasis, particularly in PNI. Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

  5. Afatinib Dimaleate and Capecitabine in Treating Patients With Advanced Refractory Solid Tumors, Pancreatic Cancer or Biliary Cancer

    ClinicalTrials.gov

    2017-08-04

    Advanced Malignant Solid Neoplasm; Bile Duct Carcinoma; Recurrent Malignant Solid Neoplasm; Recurrent Pancreatic Carcinoma; Stage III Pancreatic Cancer AJCC v6 and v7; Stage IVA Pancreatic Cancer; Stage IVB Pancreatic Cancer

  6. Quantification of esophageal tumor motion on cine-magnetic resonance imaging.

    PubMed

    Lever, Frederiek M; Lips, Irene M; Crijns, Sjoerd P M; Reerink, Onne; van Lier, Astrid L H M W; Moerland, Marinus A; van Vulpen, Marco; Meijer, Gert J

    2014-02-01

    To quantify the movement of esophageal tumors noninvasively on cine-magnetic resonance imaging (MRI) by use of a semiautomatic method to visualize tumor movement directly throughout multiple breathing cycles. Thirty-six patients with esophageal tumors underwent MRI. Tumors were located in the upper (8), middle (7), and lower (21) esophagus. Cine-MR images were collected in the coronal and sagittal plane during 60 seconds at a rate of 2 Hz. An adaptive correlation filter was used to automatically track a previously marked reference point. Tumor movement was measured in the craniocaudal (CC), left-right (LR), and anteroposterior (AP) directions and its relationship along the longitudinal axis of the esophagus was investigated. Tumor registration within the individual images was typically done at a millisecond time scale. The mean (SD) peak-to-peak displacements in the CC, AP, and LR directions were 13.3 (5.2) mm, 4.9 (2.5) mm, and 2.7 (1.2) mm, respectively. The bandwidth to cover 95% of excursions from the mean position (c95) was also calculated to exclude outliers caused by sporadic movements. The mean (SD) c95 values were 10.1 (3.8) mm, 3.7 (1.9) mm, and 2.0 (0.9) mm in the CC, AP, and LR dimensions. The end-exhale phase provided a stable position in the respiratory cycle, compared with more variety in the end-inhale phase. Furthermore, lower tumors showed more movement than did higher tumors in the CC and AP directions. Intrafraction tumor movement was highly variable between patients. Tumor position proved the most stable during the respiratory cycle in the end-exhale phase. A better understanding of tumor motion makes it possible to individualize radiation delivery strategies accordingly. Cine-MRI is a successful noninvasive modality to analyze motion for this purpose in the future. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Quantification of Esophageal Tumor Motion on Cine-Magnetic Resonance Imaging

    SciTech Connect

    Lever, Frederiek M.; Lips, Irene M.; Crijns, Sjoerd P.M.; Reerink, Onne; Lier, Astrid L.H.M.W. van; Moerland, Marinus A.; Vulpen, Marco van; Meijer, Gert J.

    2014-02-01

    Purpose: To quantify the movement of esophageal tumors noninvasively on cine-magnetic resonance imaging (MRI) by use of a semiautomatic method to visualize tumor movement directly throughout multiple breathing cycles. Methods and Materials: Thirty-six patients with esophageal tumors underwent MRI. Tumors were located in the upper (8), middle (7), and lower (21) esophagus. Cine-MR images were collected in the coronal and sagittal plane during 60 seconds at a rate of 2 Hz. An adaptive correlation filter was used to automatically track a previously marked reference point. Tumor movement was measured in the craniocaudal (CC), left–right (LR), and anteroposterior (AP) directions and its relationship along the longitudinal axis of the esophagus was investigated. Results: Tumor registration within the individual images was typically done at a millisecond time scale. The mean (SD) peak-to-peak displacements in the CC, AP, and LR directions were 13.3 (5.2) mm, 4.9 (2.5) mm, and 2.7 (1.2) mm, respectively. The bandwidth to cover 95% of excursions from the mean position (c95) was also calculated to exclude outliers caused by sporadic movements. The mean (SD) c95 values were 10.1 (3.8) mm, 3.7 (1.9) mm, and 2.0 (0.9) mm in the CC, AP, and LR dimensions. The end-exhale phase provided a stable position in the respiratory cycle, compared with more variety in the end-inhale phase. Furthermore, lower tumors showed more movement than did higher tumors in the CC and AP directions. Conclusions: Intrafraction tumor movement was highly variable between patients. Tumor position proved the most stable during the respiratory cycle in the end-exhale phase. A better understanding of tumor motion makes it possible to individualize radiation delivery strategies accordingly. Cine-MRI is a successful noninvasive modality to analyze motion for this purpose in the future.

  8. Visualization of Tumor's Vascularity for HIFU Treatment with Tissue Motion Correction

    NASA Astrophysics Data System (ADS)

    Yoshikawa, Hideki; Azuma, Takashi; Sasaki, Kazuaki; Kawabata, Ken-ichi; Umemura, Shin-ichiro

    2006-05-01

    We developed a method for visualizing the vascularity of a tumor filled with contrast agents, which cannot be clearly seen in conventional harmonic images because of the low density of microbubble contrast agents. We investigated a time-averaging method by using multiple frames with tissue motion correction. For the measurement of tissue motion, we divide an image into extremely small regions so that the loss of correlation caused by tissue motion decreases. We applied the time-averaging method to both normal rabbit kidneys and tumor implanted in rabbit muscle. For the normal kidney, the renal vascularity, including the small vessels in the renal cortex, could be clearly seen without any motion artifacts, which cannot be seen in conventional images. For the tumor implanted in rabbit muscle, neovascularity could be seen more clearly than in conventional images. We also found that by averaging multiple frames of the moving tissue, speckles were reduced and static signals were enhanced, because the signals in the slice direction were compounded. With these results, we found that the time-averaging method is useful for detecting tumors in early stages, and allowing HIFU treatment to be performed accurately without damaging normal parts.

  9. Focused ultrasound treatment of VX2 tumors controlled by local harmonic motion.

    PubMed

    Curiel, Laura; Huang, Yuexi; Vykhodtseva, Natalia; Hynynen, Kullervo

    2009-06-07

    The purpose of this study was to evaluate the feasibility of using localized harmonic motion (LHM) to monitor and control focused ultrasound surgery (FUS) in VX2 tumors in vivo. FUS exposures were performed on 13 VX2 tumors implanted in nine rabbits. The same transducer induced coagulation and generated a localized oscillatory motion by periodically varying the radiation force. A separate diagnostic ultrasound transducer tracked motion by cross-correlating echo signals at different instances. A threshold in motion amplitude was instituted to cease exposure. Coagulation was confirmed by T2-weighted MR images, thermal dose obtained through MR thermometry and histological examinations. For tumor locations achieving coagulation, the LHM amplitude was 9% (p = 0.04) to 57% (p < 0.0001) lower than that before exposure. Control was successful for 74 (69%) out of 108 cases, with 52 (48%) reaching the threshold and achieving coagulation and 22 (21%) never reaching threshold nor coagulating. For the 34 (31%) unsuccessful exposures, 16 (15%) never reached the threshold but coagulation occurred, and 18 (16%) reached threshold without coagulation confirmed. Noise or radio-frequency signal changes explained motion over- or underestimation in 24 (22%) cases; the remaining 10 (9%) had other causes of error. The control was generally successful, but sudden change or noise in the acquired echo signal caused failure. Coagulation after exposure could be validated by comparing amplitudes before and after exposure.

  10. Analysis of Lung Tumor Motion in a Large Sample: Patterns and Factors Influencing Precise Delineation of Internal Target Volume.

    PubMed

    Knybel, Lukas; Cvek, Jakub; Molenda, Lukas; Stieberova, Natalie; Feltl, David

    2016-11-15

    To evaluate lung tumor motion during respiration and to describe factors affecting the range and variability of motion in patients treated with stereotactic ablative radiation therapy. Log file analysis from online respiratory tumor tracking was performed in 145 patients. Geometric tumor location in the lungs, tumor volume and origin (primary or metastatic), sex, and tumor motion amplitudes in the superior-inferior (SI), latero-lateral (LL), and anterior-posterior (AP) directions were recorded. Tumor motion